Bicyclic anilide spirolactam CGRP receptor antagonists

ABSTRACT

The present invention is directed to compounds of Formula I: 
                         
(where variables A 1 , A 2 , B, J, K, m, n, R 4 , R 5a , R 5b  and R 5c  are as defined herein) useful as antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the CGRP is involved, such as headache, migraine and cluster headache. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

RELATED APPLICATION DATA

This is a National filing under 35 USC 371 of PCT/US2005/032041, filedSep. 9, 2005, which claims priority from U.S. Ser. No. 60/609,292, filedSep. 13, 2004.

BACKGROUND OF THE INVENTION

CGRP (Calcitonin Gene-Related Peptide) is a naturally occurring 37-aminoacid peptide that is generated by tissue-specific alternate, processingof calcitonin messenger RNA and is widely distributed in the central andperipheral nervous system. CGRP is localized predominantly in sensoryafferent and central neurons and mediates several biological actions,including vasodilation. CGRP is expressed in alpha- and beta-forms thatvary by one and three amino acids in the rat and human, respectively.CGRP-alpha and CGRP-beta display similar biological properties. Whenreleased from the cell, CGRP initiates its biological responses bybinding to specific cell surface receptors that are predominantlycoupled to the activation of adenylyl cyclase. CGRP receptors have beenidentified and pharmacologically evaluated in several tissues and cells,including those of brain, cardiovascular, endothelial, and smooth muscleorigin.

Based on pharmacological properties, these receptors are divided into atleast two subtypes, denoted CGRP₁ and CGRP₂. Human □-CGRP-(8-37), afragment of CGRP that lacks seven N-terminal amino acid residues, is aselective antagonist of CGRP₁, whereas the linear analogue of CGRP,diacetoamido methyl cysteine CGRP ([Cys(ACM)2,7]CGRP), is a selectiveagonist of CGRP₂. CGRP is a potent vasodilator that has been implicatedin the pathology of cerebrovascular disorders such as migraine andcluster headache. In clinical studies, elevated levels of CGRP in thejugular vein were found to occur during migraine attacks (Goadsby etal., Ann. Neurol., 1990, 28, 183-187). CGRP activates receptors on thesmooth muscle of intracranial vessels, leading to increasedvasodilation, which is thought to be the major source of headache painduring migraine attacks (Lance, Headache Pathogenesis: Monoamines,Neuropeptides, Purines and Nitric Oxide, Lippincott-Raven Publishers,1997, 3-9). The middle meningeal artery, the principle artery in thedura mater, is innervated by sensory fibers from the trigeminal ganglionwhich contain several neuropeptides, including CGRP. Trigeminal ganglionstimulation in the cat resulted in increased levels of CGRP, and inhumans, activation of the trigeminal system caused facial flushing andincreased levels of CGRP in the external jugular vein (Goadsby et al.,Ann. Neurol., 1988, 23, 193-196). Electrical stimulation of the duramater in rats increased the diameter of the middle meningeal artery, aneffect that was blocked by prior administration of CGRP(8-37), a peptideCGRP antagonist (Williamson et al., Cephalalgia, 1997, 17, 525-531).Trigeminal ganglion stimulation increased facial blood flow in the rat,which was inhibited by CGRP(8-37) (Escott et al., Brain Res. 1995, 669,93-99). Electrical stimulation of the trigeminal ganglion in marmosetproduced an increase in facial blood flow that could be blocked by thenon-peptide CGRP antagonist BIBN4096BS (Doods et al., Br. J. Pharmacol.,2000, 129, 420-423). Thus the vascular effects of CGRP may beattenuated, prevented or reversed by a CGRP antagonist.

CGRP-mediated vasodilation of rat middle meningeal artery was shown tosensitize neurons of the trigeminal nucleus caudalis (Williamson et al.,The CGRP Family: Calcitonin Gene-Related Peptide (CGRP), Amylin, andAdrenomedullin, Landes Bioscience, 2000, 245-247). Similarly, distentionof dural blood vessels during migraine headache may sensitize trigeminalneurons. Some of the associated symptoms of migraine, includingextra-cranial pain and facial allodynia, may be the result of sensitizedtrigeminal neurons (Burstein et al., Ann. Neurol. 2000, 47, 614-624). ACGRP antagonist may be beneficial in attenuating, preventing orreversing the effects of neuronal sensitization.

The ability of the compounds of the present invention to act as CGRPantagonists makes them useful pharmacological agents for disorders thatinvolve CGRP in humans and animals, but particularly in humans. Suchdisorders include migraine and cluster headache (Doods, Curr Opin InvesDrugs, 2001, 2 (9), 1261-1268; Edvinsson et al., Cephalalgia, 1994, 14,320-327); chronic tension type headache (Ashina et al., Neurology, 2000,14, 1335-1340); pain (Yu et al., Eur. J. Pharm., 1998, 347, 275-282);chronic pain (Hulsebosch et al., Pain, 2000, 86, 163-175); neurogenicinflammation and inflammatory pain (Holzer, Neurosci., 1988, 24,739-768; Delay-Goyet et al., Acta Physiol. Scanda. 1992, 146, 537-538;Salmon et al., Nature Neurosci., 2001, 4(4), 357-358); eye pain (May etal. Cephalalgia, 2002, 22, 195-196), tooth pain (Awawdeh et al., Int.Endocrin. J., 2002, 35, 30-36), non-insulin dependent diabetes mellitus(Molina et al., Diabetes, 1990, 39, 260-265); vascular disorders;inflammation (Zhang et al., Pain, 2001, 89, 265), arthritis, bronchialhyperreactivity, asthma, (Foster et al., Ann. NY Acad. Sci., 1992, 657,397-404; Schini et al., Am. J. Physiol., 1994, 267, H2483-H2490; Zhenget al., J. Virol., 1993, 67, 5786-5791); shock, sepsis (Beer et al.,Crit. Care Med., 2002, 30 (8), 1794-1798); opiate withdrawal syndrome(Salmon et al., Nature Neurosci., 2001, 4(4), 357-358) morphinetolerance (Menard et al., J. Neurosci., 1996, 16 (7), 2342-2351); hotflashes in men and women (Chen et al., Lancet, 1993, 342, 49; Spetz etal., J. Urology, 2001, 166, 1720-1723); allergic dermatitis (Wallengren,Contact Dermatitis, 2000, 43 (3), 137-143); psoriasis; encephalitis,brain trauma, ischaemia, stroke, epilepsy, and neurodegenerativediseases (Rohrenbeck et al., Neurobiol. of Disease 1999, 6, 15-34); skindiseases (Geppetti and Holzer, Eds., Neurogenic Inflammation, 1996, CRCPress, Boca Raton, Fla.), neurogenic cutaneous redness, skinrosaceousness and erythema; tinnitus (Herzog et al., J. MembraneBiology, 2002, 189(3), 225); inflammatory bowel disease, irritable bowelsyndrome, (Hoffman et al. Scandinavian Journal of Gastroenterology,2002, 37(4) 414-422) and cystitis. Of particular importance is the acuteor prophylactic treatment of headache, including migraine and clusterheadache. Compelling evidence of the efficacy of CGRP antagonists forthe treatment of migraine has been provided by clinical studies usingintravenously administered BIBN4096BS. This CGRP antagonist was found tobe a safe and effective acute treatment for migraine (Olesen et al., N.Engl. J. Med., 2004, 350(11), 1104-1110).

The present invention relates to compounds that are useful as ligandsfor CGRP receptors, in particular antagonists for CGRP receptors,processes for their preparation, their use in therapy, pharmaceuticalcompositions comprising them and methods of therapy using them.

SUMMARY OF THE INVENTION

The present invention is directed to compounds which are antagonists ofCGRP receptors and which are useful in the treatment or prevention ofdiseases in which the CGRP is involved, such as migraine. The inventionis also directed to pharmaceutical compositions comprising thesecompounds and the use of these compounds and compositions in theprevention or treatment of such diseases in which CGRP is involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:

-   B is a bicycloheterocycle selected from the group consisting of:

-   -   where T, U, V, W, X and Y are each independently a carbon atom        or a nitrogen atom, wherein no more than two of T, U, V and W,        and no more than three of T, U, V, W, X and Y, are a nitrogen        atoms,

-   B is unsubstituted or substituted with 1-5 substituents each    independently selected from R¹, R², R^(3a) and R^(3b), wherein R¹,    R², R^(3a) and R^(3b) are independently selected from:    -   (1) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-7        substituents each independently selected from:        -   (a) halo,        -   (b) hydroxy,        -   (c) —O—C₁₋₆alkyl,        -   (d) —C₃₋₆cycloalkyl,        -   (e) phenyl or heterocycle, wherein heterocycle is selected            from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,            piperidinyl, piperazinyl, pyrrolidinyl, oxazolyl, thiazolyl,            thienyl and morpholinyl, which phenyl or heterocycle is            unsubstituted or substituted with 1-5 substituents each            independently selected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo,            hydroxy, trifluoromethyl and —OCF₃,        -   (f) —CO₂R⁹, wherein R⁹ is independently selected from:            hydrogen, —C₁₋₆alkyl which is unsubstituted or substituted            with 1-6 fluoro, —C₃₋₆cycloalkyl, benzyl and phenyl,        -   (g) —NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are each independently            selected from:            -   hydrogen, —C₁₋₆alkyl which is unsubstituted or                substituted with 1-6 fluoro, —C₅₋₆cycloalkyl, benzyl,                phenyl, —COR⁹ and —SO₂R¹²,        -   (h) —SO₂R¹², wherein R¹² is independently selected from:            —C₁₋₆alkyl, which is unsubstituted or substituted with 1-6            fluoro, —C₅₋₆cycloalkyl, benzyl and phenyl,        -   (i) —CONR^(10a)R^(11a), wherein R^(10a) and R^(11a) are each            independently selected from:            -   hydrogen, —C₁₋₆alkyl which is unsubstituted or                substituted with 1-6 fluoro, —C₅₋₆cycloalkyl, benzyl and                phenyl,            -   or R^(10a) and R^(11a) are joined to form a ring                selected from azetidinyl, pyrrolidinyl, piperidinyl,                piperazinyl and morpholinyl, which ring is unsubstituted                or substituted with 1-5 substituents each independently                selected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo, hydroxyl,                phenyl and benzyl,        -   (j) trifluoromethyl,        -   (k) —OCO₂R⁹,        -   (l) —(NR^(10a))CO₂R⁹,        -   (m) —O(CO)NR^(10a)R^(11a),        -   (n) —(NR⁹)(CO)NR^(10a)R^(11a), and        -   (o) —O—C₃₋₆cycloalkyl,    -   (2) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with        1-7 substituents each independently selected from:        -   (a) halo,        -   (b) hydroxy,        -   (c) —O—C₁₋₆alkyl,        -   (d) trifluoromethyl,        -   (e) phenyl, which is unsubstituted or substituted with 1-5            substituents each independently selected from: —C₁₋₆alkyl,            —O—C₁₋₆alkyl, halo, hydroxy and trifluoromethyl,    -   (3) phenyl or heterocycle, wherein heterocycle is selected from:        pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl,        pyrrolidinyl, azetidinyl, thiazolyl, isothiazolyl, oxazolyl,        isoxazolyl, imidazolyl, triazolyl, tetrazolyl, azepanyl,        benzimidazolyl, benzopyranyl, benzofuryl, benzothiazolyl,        benzoxazolyl, chromanyl, furyl, imidazolinyl, indolinyl,        indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,        isoindolinyl, tetrahydroisoquinolinyl, 2-oxopiperazinyl,        2-oxopiperidinyl, 2-oxopyrrolidinyl, pyrazolidinyl, pyrazolyl,        pyrrolyl, quinazolinyl, tetrahydrofuryl, thiazolinyl, purinyl,        naphthyridinyl, quinoxalinyl, 1,3-dioxolanyl, oxadiazolyl,        piperidinyl, tetrahydropyranyl, tetrahydrothienyl,        tetrahydrothiopyranyl, and morpholinyl, which phenyl or        heterocycle is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 fluoro,        -   (b) halo,        -   (c) hydroxy,        -   (d) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 fluoro,        -   (e) —C₃₋₆cycloalkyl,        -   (f) phenyl or heterocycle, wherein heterocycle is selected            from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, or            morpholinyl,            -   which is unsubstituted or substituted with 1-5                substituents where the substituents are independently                selected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo, hydroxy                and trifluoromethyl,        -   (g) —CO₂R⁹,        -   (h) —(CO)R⁹,        -   (i) —NR¹⁰R¹¹,        -   (j) —CONR¹⁰R¹¹,        -   (k) oxo        -   (l) —SR¹²,        -   (m) —S(O)R¹², and        -   (n) —SO₂R¹²,    -   (4) halo,    -   (5) oxo,    -   (6) hydroxy,    -   (7) —O—C₁₋₆alkyl which is unsubstituted or substituted with 1-5        halo,    -   (8) —CN,    -   (9) —CO₂R⁹,    -   (10) —NR¹⁰R¹¹,    -   (11) —SO₂R¹²,    -   (12) —CONR^(10a)R^(11a),    -   (13) —OCO₂R⁹,    -   (14) —(NR^(10a))CO₂R⁹,    -   (15) —O(CO)NR^(10a)R^(11a),    -   (16) —(NR⁹)(CO)NR^(10a)R^(11a),    -   (17) —(CO)—(CO)NR^(10a)R^(11a),    -   (18) —(CO)—(CO)OR⁹, and    -   (19) —SO₂NR^(10a)R^(11a);    -   or R^(3a) and R^(3b) and the carbon atom(s) to which they are        attached are joined to form a ring selected from cyclobutyl,        cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl,        azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl,        tetrahydropyranyl, furanyl, dihydrofuranyl, dihydropyranyl,        thienyl, dihydrothienyl, tetrahydrothienyl, dihydrothiopyranyl,        tetrahydrothiopyranyl and piperazinyl, which ring is        unsubstituted or substituted with 1-5 substituents each        independently selected from:        -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-3 substituents each independently selected from:            -   (i) halo,            -   (ii) hydroxy,            -   (iii) —O—C₁₋₆alkyl,            -   (iv) —C₃₋₆cycloalkyl,            -   (v) phenyl or heterocycle, wherein heterocycle is                selected from: pyridyl, pyrimidinyl, pyrazinyl,                pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl,                thienyl and morpholinyl, which phenyl or heterocycle is                unsubstituted or substituted with 1-5 substituents each                independently selected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl,                halo, hydroxy, trifluoromethyl and —OCF₃,            -   (vi) —CO₂R⁹,            -   (vii) —NR¹⁰R¹¹,            -   (viii) —SO₂R¹²,            -   (ix) —CONR^(10a)R^(11a), and            -   (x) —(NR^(10a))CO₂R⁹,        -   (b) phenyl or heterocycle, wherein heterocycle is selected            from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl,            pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl, which            phenyl or heterocycle is unsubstituted or substituted with            1-3 substituents each independently selected from:            —C₁₋₆alkyl which is unsubstituted or substituted with 1-6            fluoro, halo, hydroxy, —O—C₁₋₆alkyl, which is unsubstituted            or substituted with 1-6 fluoro, and —C₃₋₆cycloalkyl,        -   (c) halo,        -   (d) —SO₂R¹²,        -   (e) hydroxy,        -   (f) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            1-5 halo,        -   (g) —CN,        -   (h) —COR¹²,        -   (i) —NR¹⁰R¹¹,        -   (j)—CONR^(10a)R^(11a),        -   (k) —CO₂R⁹,        -   (l) —(NR^(10a))CO₂R⁹,        -   (m) —O(CO)NR^(10a)R^(11a),        -   (n) —(NR⁹)(CO)NR^(10a)R^(11a), and        -   (o) oxo;

-   A¹ and A² are each independently selected from: a bond and    —CR¹³R¹⁴—,    -   wherein R¹³ and R¹⁴ are each independently selected from:        hydrogen, C₁₋₆ alkyl which is unsubstituted or substituted with        1-6 fluoro, hydroxy and halo,

-   wherein one of A¹ and A² is optionally absent;

-   J is independently selected from: ═C(R^(6a))—, —CR¹³R¹⁴— and    —C(═O)—;

-   K is independently selected from: ═C(R^(6b))—, —CR¹³R¹⁴—, —C(═O)—,    —SO₂—, ═N— and —N(R^(6b))—;

-   R⁴ is independently selected from: hydrogen, C₁₋₆ alkyl which is    unsubstituted or substituted with 1-6 fluoro, C₅₋₆ cycloalkyl,    benzyl and phenyl;

-   R^(5a), R^(5b) and R^(5c) are each independently selected from:    hydrogen, C₁₋₆ alkyl, —O—C₁₋₆alkyl, —OCF₃, trifluoromethyl, halo,    hydroxy and —CN;

-   R^(6a) and R^(6b) are each independently selected from:    -   (1) hydrogen;    -   (2) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) halo,        -   (b) —O—C₁₋₆alkyl,        -   (c) —C₃₋₆cycloalkyl,        -   (d) phenyl or heterocycle, wherein heterocycle is selected            from: imidazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl,            pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl,            thiazolyl, thienyl, triazolyl and morpholinyl, which phenyl            or heterocycle is unsubstituted or substituted with 1-3 each            independently selected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo,            hydroxy, trifluoromethyl and —OCF₃,    -   (3) phenyl or heterocycle, wherein heterocycle is selected from:        pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl,        azetidinyl, thiazolyl, oxazolyl, imidazolyl, triazolyl,        tetrahydrofuryl, piperidinyl, and morpholinyl, which phenyl or        heterocycle is unsubstituted or substituted with 1-3        substituents each independently selected from: —C₁₋₄alkyl which        is unsubstituted or substituted with 1-5 fluoro, —O—C₁₋₄alkyl,        which is unsubstituted or substituted with 1-5 fluoro, halo,        hydroxy, —C₃₋₆cycloalkyl and phenyl,    -   (4) halo,    -   (5) hydroxy,    -   (6) —O—C₁₋₆alkyl which is unsubstituted or substituted with 1-5        halo,    -   (7) —CN,    -   (8) —CO₂R⁹,    -   (9) —NR¹⁰R¹¹, and    -   (10) —CONR^(10a)R^(11a);

-   or R^(6a) and R^(6b) and the atom(s) to which they are attached are    joined to form a ring selected from cyclopentenyl, cyclohexenyl,    phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl,    dihydrofuranyl, dihydropyranyl, thiazolyl, isothiazolyl, oxazolyl,    isoxazolyl, imidazolyl, triazolyl, thienyl, dihydrothienyl and    dihydrothiopyranyl, which ring is unsubstituted or substituted with    1-5 substituents each independently selected from:    -   (a) —C₁₋₆alkyl which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (i) halo,        -   (ii) hydroxy,        -   (iii) —O—C₁₋₆alkyl,        -   (iv) —C₃₋₆cycloalkyl,        -   (v) phenyl or heterocycle, wherein heterocycle is selected            from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,            piperidinyl, piperazinyl, pyrrolidinyl, thienyl and            morpholinyl, which phenyl or heterocycle is unsubstituted or            substituted with 1-5 substituents each independently            selected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo, hydroxy,            trifluoromethyl and —OCF₃,        -   (vi) —CO₂R⁹,        -   (vii) —NR¹⁰R¹¹,        -   (viii) —SO₂R¹²,        -   (ix) —CONR^(10a)R^(11a) and        -   (x) —(NR^(10a))CO₂R⁹,    -   (b) phenyl or heterocycle, wherein heterocycle is selected from:        pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl,        pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl, which        phenyl or heterocycle is unsubstituted or substituted with 1-3        substituents each independently selected from: —C₁₋₆alkyl which        is unsubstituted or substituted with 1-6 fluoro, —O—C₁₋₆alkyl        which is unsubstituted or substituted with 1-6 fluoro, halo,        hydroxyl and —C₃₋₆cycloalkyl,    -   (c) halo,    -   (d) —SO₂R¹²,    -   (e) hydroxy,    -   (f) —O—C₁₋₆alkyl which is unsubstituted or substituted with 1-5        halo,    -   (g) —CN,    -   (h) —COR¹²,    -   (i) —NR¹⁰R¹¹,    -   (i) —CONR^(10a)R^(11a),    -   (k) —CO₂R⁹,    -   (l) —(NR^(10a))CO₂R⁹,    -   (m) —O(CO)NR^(10a)R^(11a),    -   (n) —(NR⁹)(CO)NR^(10a)R^(11a), and    -   (o) oxo;

-   m is 1 or 2;

-   n is 1 or 2;

-   and pharmaceutically acceptable salts thereof and individual    enantiomers and diastereomers thereof.

An embodiment of the present invention includes compounds of the formulaIa:

wherein A¹, A², B, J, K, R⁴, m, and n are defined herein;

-   and pharmaceutically acceptable salts thereof and individual    enantiomers and diastereomers thereof.

Another embodiment of the present invention includes compounds of theformula Ib:

wherein B, J, K, R⁴, m, and n are defined herein;

-   and pharmaceutically acceptable salts thereof and individual    enantiomers and diastereomers thereof.

Another embodiment of the present invention includes compounds of theformula Ic:

wherein B, J, and K are defined herein;

-   and pharmaceutically acceptable salts thereof and individual    enantiomers and diastereomers thereof.

Another embodiment of the present invention includes compounds of theformula Id:

wherein B, J, and K are defined herein;

-   and pharmaceutically acceptable salts thereof and individual    enantiomers and diastereomers thereof.

Another embodiment of the present invention includes compounds of theformula Ie:

wherein B is defined herein;

-   and pharmaceutically acceptable salts thereof and individual    enantiomers and diastereomers thereof.

Another embodiment of the present invention includes compounds of theformula If:

wherein B is defined herein;

-   and pharmaceutically acceptable salts thereof and individual    enantiomers and diastereomers thereof.

Another embodiment of the present invention includes compounds of theformula Ig:

wherein B is defined herein;

-   and pharmaceutically acceptable salts thereof and individual    enantiomers and diastereomers thereof.

In an embodiment of the present invention B is selected from the groupconsisting of:

which is unsubstituted or substituted with 1-5 substituents selectedfrom R¹, R², R^(3a) and R^(3b), wherein R¹, R², R^(3a) and R^(3b) aredefined herein.

In an embodiment of the present invention B is 2-oxobenzimidazolinyl.

In an embodiment of the present invention B is indolyl.

In an embodiment of the present invention B is indolinyl.

In an embodiment of the present invention B is 2-oxoindolinyl.

In an embodiment of the present invention B is 2-oxoazabenzimidazolinyl.

In an embodiment of the present invention B is azaindolyl.

In an embodiment of the present invention R¹, R², R^(3a) and R^(3b) areindependently selected from:

-   -   (1) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) fluoro,        -   (b) phenyl or heterocycle, wherein heterocycle is selected            from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,            piperidinyl, piperazinyl, pyrrolidinyl, thienyl and            morpholinyl,        -   (c) —CO₂R⁹, wherein R⁹ is independently selected from:            hydrogen, and —C₁₋₆alkyl,        -   (d) —CONR^(10a)R^(11a), wherein R^(10a) and R¹¹a are each            independently selected from: hydrogen and —C₁₋₆alkyl,            -   or R^(10a) and R^(11a) are joined to form a ring                selected from azetidinyl, pyrrolidinyl, piperidinyl,                piperazinyl and morpholinyl, and        -   (e) —O—C₃₋₆cycloalkyl,    -   (2) phenyl or heterocycle, wherein heterocycle is selected from:        pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl,        pyrrolidinyl, thiazolyl, isothiazolyl, 2-oxopyrrolidinyl,        tetrahydrofuryl, piperidinyl, tetrahydrothienyl and        tetrahydrothiopyranyl, which phenyl or heterocycle is        unsubstituted or substituted with 1-5 substituents each        independently selected from:        -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-3 fluoro,        -   (b) halo,        -   (c) —CO₂R⁹, wherein R⁹ is selected from: hydrogen,            —C₁₋₄alkyl, and —C₃₋₆cycloalkyl,        -   (d) —(CO)R⁹,        -   (e) CONR^(10a)R^(11a), wherein R^(10a) and R^(11a) are            independently selected from: hydrogen and —C₁₋₆alkyl,            -   or R^(10a) and R^(11a) are joined to form a ring                selected from azetidinyl, pyrrolidinyl, piperidinyl,                piperazinyl, and morpholinyl,        -   (f) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            1-3 fluoro,        -   (g) hydroxy,        -   (h) oxo,        -   (i) —S—C₁₋₄alkyl,        -   (j) —S(O)—C₁₋₄alkyl, and        -   (k) —SO₂—C₁₋₄alkyl,    -   (3) halo,    -   (4) hydroxy,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-3        fluoro,    -   (6) —NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are each independently        selected from: hydrogen, —C₁₋₄alkyl which is unsubstituted or        substituted with 1-5 fluoro, —C₅₋₆cycloalkyl, and —COR⁹, wherein        R⁹ is defined herein.    -   (7) —C₃₋₆cycloalkyl,    -   (8) —(CO)—(CO)NR^(10a)R^(11a), wherein R^(10a) and R^(11a) are        independently selected from:        -   hydrogen and —C₁₋₆alkyl, and    -   (9) —CN.

In an embodiment of the present invention R¹ and R² are independentlyselected from:

-   -   (1) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) fluoro,        -   (b) phenyl,        -   (c) —CO₂R⁹, wherein R⁹ is independently selected from:            hydrogen and —C₁₋₁₄alkyl,        -   (d) —CONR^(10a)R^(11a), wherein R^(10a) and R^(11a) are each            independently selected from:            -   hydrogen and —C₁₋₁₄alkyl,            -   or R^(10a) and R^(11a) are joined to form a ring                selected from azetidinyl, pyrrolidinyl, piperidinyl,                piperazinyl, and morpholinyl, and        -   (e) —O—C₃₋₆cycloalkyl,    -   (2) phenyl or heterocycle, wherein heterocycle is selected from:        pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolidinyl,        thiazolyl, tetrahydrofuryl, piperidinyl and        tetrahydrothiopyranyl, which phenyl or heterocycle is        unsubstituted or substituted with 1-5 substituents each        independently selected from:        -   (a) —C₁₋₄alkyl, which is unsubstituted or substituted with            1-3 fluoro        -   (b) halo,        -   (c) —CO₂R⁹, wherein R⁹ is selected from: hydrogen,            —C₁₋₄alkyl, and —C₃₋₆cycloalkyl,        -   (d) —(CO)R⁹,        -   (e) —CONR^(10a)R^(11a), wherein R^(10a) and R^(11a) are            independently selected from:            -   hydrogen and —C₁₋₄alkyl,        -   (f) —O—C₁₋₄alkyl, which is unsubstituted or substituted with            1-3 fluoro,        -   (g) hydroxy,        -   (h) oxo        -   (i) —S—C₁₋₄alkyl,        -   (j) —S(O)—C₁₋₄alkyl, and        -   (k) —SO₂—C₁₋₄alkyl,    -   (3) halo,    -   (4) hydroxy,    -   (5) —O—C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        fluoro,    -   (6) —CN,    -   (7) —C₃₋₆cycloalkyl,    -   (8) —(CO)—(CO)NR^(10a)R^(11a), wherein R^(10a) and R^(11a) are        independently selected from:        -   hydrogen and —C₁₋₄alkyl, and    -   (9) —NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are each independently        selected from: hydrogen, —C₁₋₄alkyl, and —COR⁹, wherein R⁹ is        defined herein.

In an embodiment of the present invention, R^(3a) and R^(3b) and thecarbon atom(s) to which they are attached are joined together to form aring selected from piperidinyl, cyclohexyl, cyclopentyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, andtetrahydrothiopyranyl, which is unsubstituted or substituted with 1-3substituents independently selected from:

-   -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-3        substituents where the substituents are independently selected        from:        -   (i) halo, and        -   (ii) phenyl,    -   (b) phenyl or heterocycle, wherein heterocycle is selected from:        pyridyl, pyrimidinyl and pyrazinyl,    -   (c) —CO₂R⁹, wherein R⁹ is selected from:        -   (i) hydrogen, and        -   (ii) —C₁₋₄alkyl.    -   (d) hydroxy, and    -   (e) oxo.

In an embodiment of the present invention, R^(3a) and R^(3b) and thecarbon atom(s) to which they are attached are joined together to form aring selected from piperidinyl, cyclohexyl, tetrahydropyranyl, andtetrahydrothiopyranyl, which ring is unsubstituted or substituted with1-3 substituents each independently selected from:

-   -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-3        substituents independently selected from: fluoro and phenyl,    -   (b) —CO₂—C₁₋₄alkyl,    -   (c) hydroxyl, and    -   (d) oxo.

In an embodiment of the present invention A¹ is a bond.

In an embodiment of the present invention A² is —CH₂—.

In an embodiment of the present invention J is selected from:═C(R^(6a))—; and —CH₂—; wherein R^(6a) is defined herein.

In an embodiment of the present invention J is —CH₂—.

In an embodiment of the present invention J is ═C(R^(6a))—; whereinR^(6a) is defined herein.

In an embodiment of the present invention K is selected from:═C(R^(6b))—; —CH₂—; and —C(═O)—; wherein R^(6b) is defined herein.

In an embodiment of the present invention K is —CH₂—.

In an embodiment of the present invention K is ═C(R^(6b))—; whereinR^(6b) is defined herein.

In an embodiment of the present invention R⁴ is selected from: hydrogenand —C₁₋₆alkyl, which is unsubstituted or substituted with fluoro.

In an embodiment of the present invention R⁴ is hydrogen.

In an embodiment of the present invention R^(5a), R^(5b) and R^(5c) areindependently selected from hydrogen, C₁₋₆alkyl and halo.

In an embodiment of the present invention R^(5a), R^(5b) and R^(5c) areindependently selected from hydrogen and halo.

In an embodiment of the present invention R^(5a), R^(5b) and R^(5c) arehydrogen.

In an embodiment of the present invention R^(6a) and R^(6b) areindependently selected from:

-   -   (1) hydrogen;    -   (2) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from: halo,        —O—C₁₋₆alkyl, —C₃₋₆cycloalkyl, and phenyl,    -   (3) phenyl or heterocycle, wherein heterocycle is selected from:        pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl,        tetrahydrofuryl, piperidinyl, and morpholinyl, which phenyl or        heterocycle is unsubstituted or substituted with 1-3        substituents where the substituents are each independently        selected from: —C₁₋₄alkyl which is unsubstituted or substituted        with 1-3 fluoro, —O—C₁₋₄alkyl, which is unsubstituted or        substituted with 1-3 fluoro, halo and hydroxyl,    -   (4) halo,    -   (5) —NR¹⁰R¹¹,    -   (6) hydroxy,    -   (7) —O—C₁₋₄alkyl which is unsubstituted or substituted with 1-3        halo.

In an embodiment of the present invention R^(6a) and R^(6b) areindependently selected from:

-   -   (1) hydrogen;    -   (2) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        fluoro, and    -   (3) phenyl or heterocycle, wherein heterocycle is selected from:        pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl,        tetrahydrofuryl, piperidinyl, and morpholinyl.

In an embodiment of the present invention R^(6a) and R^(6b) and theatom(s) to which they are attached are joined to form a ring selectedfrom phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl,oxazolyl, imidazolyl and thienyl, which ring is unsubstituted orsubstituted with 1-3 substituents each independently selected from:

-   -   (a) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from: halo,        —O—C₁₋₆alkyl, —CO₂R⁹, —NR¹⁰R¹¹ and CONR^(10a)R^(11a),    -   (b) phenyl or heterocycle, wherein heterocycle is selected from:        pyridyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, azetidinyl,        piperidinyl and morpholinyl, which phenyl or heterocycle is        unsubstituted or substituted with 1-3 substituents each        independently selected from: —C₁₋₄alkyl, which is unsubstituted        or substituted with 1-5 fluoro, —O—C₁₋₄alkyl, which is        unsubstituted or substituted with 1-3 fluoro, halo and hydroxyl,    -   (c) halo,    -   (d) hydroxy,    -   (e) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        halo,    -   (f) —CN,    -   (g) —NR¹⁰R¹¹,    -   (h) —CONR^(10a)R^(11a), and    -   (i) oxo.

In an embodiment of the present invention R^(6a) and R^(6b) and theatom(s) to which they are attached are joined to form a ring selectedfrom phenyl, pyridyl, and pyrimidinyl, which ring is unsubstituted orsubstituted with 1-3 substituents each independently selected from:—C₁₋₄alkyl which is unsubstituted or substituted with 1-3 fluoro, halo,hydroxy and —O—C₁₋₄alkyl.

In an embodiment of the present invention R^(6a) and R^(6b) and theatom(s) to which they are attached are joined to form a ring selectedfrom pyridyl, and pyrimidinyl.

In an embodiment of the present invention m is 1.

In an embodiment of the present invention n is 1.

In an embodiment of the present invention n is 2.

It is to be understood that where one or more of the above recitedstructures or substructures recite multiple substituents having the samedesignation each such variable may be the same or different from eachsimilarly designated variable. The invention is not limited tostructures and substructures wherein each instance of a particularvariable must represent the same moiety or substructure.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

As will be appreciated by those of skill in the art, not all of theR^(10a) and R^(11a) substituents are capable of forming a ringstructure. Moreover, even those substituents capable of ring formationmay or may not form a ring structure.

Also as appreciated by those of skill in the art, halo or halogen asused herein are intended to include chloro, fluoro, bromo and iodo.

As used herein, “alkyl” is intended to mean linear, branched and cyclicstructures having no double or triple bonds. Thus C₁₋₆alkyl is definedto identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linearor branched arrangement, such that C₁₋₆alkyl specifically includesmethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl,pentyl and hexyl. “Cycloalkyl” is an alkyl, part or all of which whichforms a ring of three or more atoms. C₀ or C₀alkyl is defined toidentify the presence of a direct covalent bond.

As used herein, “aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of up to 7 members in each ring, wherein at leastone ring is aromatic. Examples of such aryl elements include phenyl,napthyl, tetrahydronapthyl, indanyl, or biphenyl.

The term “heterocycle” or “heterocyclic”, as used herein except wherenoted, represents a stable 5- to 7-membered monocyclic- or stable 8- to11-membered bicyclic heterocyclic ring system which is either saturatedor unsaturated, and which consists of carbon atoms and from one to fourheteroatoms selected from the group consisting of N, O and S, andwherein the nitrogen and sulfur heteroatoms may optionally be oxidized,and the nitrogen heteroatom may optionally be quaternized, and includingany bicyclic group in which any of the above-defined heterocyclic ringsis fused to a benzene ring. The heterocyclic ring may be attached at anyheteroatom or carbon atom which results in the creation of a stablestructure. Examples of such heterocyclic groups include, but are notlimited to, azetidine, chroman, dihydrofuran, dihydropyran, dioxane,dioxolane, hexahydroazepine, imidazolidine, imidazolidinone,imidazoline, imidazolinone, indoline, isochroman, isoindoline,isothiazoline, isothiazolidine, isoxazoline, isoxazolidine, morpholine,morpholinone, oxazoline, oxazolidine, oxazolidinone, oxetane,2-oxohexahydroazepin, 2-oxopiperazine, 2-oxopiperidine,2-oxopyrrolidine, piperazine, piperidine, pyran, pyrazolidine,pyrazoline, pyrrolidine, pyrroline, quinuclidine, tetrahydrofuran,tetrahydropyran, thiamorpholine, thiazoline, thiazolidine,thiomorpholine and N-oxides thereof.

The term “heteroaryl”, as used herein except where noted, represents astable 4- to 7-membered monocyclic- or stable 9- to 10-membered fusedbicyclic heterocyclic ring system which contains an aromatic ring, anyring of which may be saturated, such as piperidinyl, partiallysaturated, or unsaturated, such as pyridinyl, and which consists ofcarbon atoms and from one to four heteroatoms selected from the groupconsisting of N, O and S, and wherein the nitrogen and sulfurheteroatoms may optionally be oxidized, and the nitrogen heteroatom mayoptionally be quaternized, and including any bicyclic group in which anyof the above-defined heterocyclic rings is fused to a benzene ring. Theheterocyclic ring may be attached at any heteroatom or carbon atom whichresults in the creation of a stable structure. Examples of suchheteroaryl groups include, but are not limited to, benzimidazole,benzisothiazole, benzisoxazole, benzofuran, benzothiazole,benzothiophene, benzotriazole, benzoxazole, carboline, cinnoline, furan,furazan, imidazole, indazole, indole, indolizine, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine,pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole,thiadiazole, thiazole, thiophene, triazine, triazole, and N-oxidesthereof.

The term “alkoxy,” as in C₁-C₆ alkoxy, is intended to refer to includealkoxy groups of from 1 to 6 carbon atoms of a straight, branched andcyclic configuration. Examples include methoxy, ethoxy, propoxy,isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativeswherein the parent compound is modified by making acid or base saltsthereof. Examples of pharmaceutically acceptable salts include, but arenot limited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts or the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, such conventional non-toxic salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,ethane disulfonic, oxalic, isethionic, and the like.

The terms “bond” and “absent” are in certain instances herein usedinterchangeably to refer to an atom (or chemical moiety) which is notpresent in a particular embodiment of the invention. In suchembodiments, the atoms adjacent the “bond” or “absent” atom are simplybonded to one another. For example, in certain embodiments of theinvention described and claimed herein, where A² is described as“absent”. In such a molecule, it is understood that A¹ is bondeddirectly to the —C(═O) moiety, resulting in the sub-structureB⁴-A¹-C(═O). The absence of a specific atom or moiety, particularly anatom or moiety which serves to link or connect other atoms or moieties,does not imply that such other atoms or moieties are not linked.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. In one aspect of the invention the salts are citric,hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, andtartaric acids. It will be understood that, as used herein, referencesto the compounds of Formula I are meant to also include thepharmaceutically acceptable salts.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein. Specific compounds within the present inventioninclude a compound which is selected from the group consisting of thecompounds disclosed in the following Examples and pharmaceuticallyacceptable salts thereof and individual diastereomers thereof.

The subject compounds are useful in a method of antagonism of CGRPreceptors in a patient such as a mammal in need of such antagonismcomprising the administration of an effective amount of the compound.The present invention is directed to the use of the compounds disclosedherein as antagonists of CGRP receptors. In addition to primates,especially humans, a variety of other mammals can be treated accordingto the method of the present invention.

Another embodiment of the present invention is directed to a method forthe treatment, control, amelioration, or reduction of risk of a diseaseor disorder in which the CGRP receptor is involved in a patient thatcomprises administering to the patient a therapeutically effectiveamount of a compound that is an antagonist of CGRP receptors.

The present invention is further directed to a method for themanufacture of a medicament for antagonism of CGRP receptors activity inhumans and animals comprising combining a compound of the presentinvention with a pharmaceutical carrier or diluent.

The subject treated in the present methods is generally a mammal, forexample a human being, male or female, in whom antagonism of CGRPreceptor activity is desired. The term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. As used herein, the term “treatment” refers both to thetreatment and to the prevention or prophylactic therapy of the mentionedconditions, particularly in a patient who is predisposed to such diseaseor disorder.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual in need of treatment.

The utility of the compounds in accordance with the present invention asantagonists of CGRP receptor activity may be demonstrated by methodologyknown in the art. Inhibition of the binding of ¹²⁵I-CGRP to receptorsand functional antagonism of CGRP receptors were determined as follows:

NATIVE RECEPTOR BINDING ASSAY: The binding of ¹²⁵I-CGRP to receptors inSK-N-MC cell membranes was carried out essentially as described(Edvinsson et al. (2001) Eur. J. Pharmacol. 415, 39-44). Briefly,membranes (25 □g) were incubated in 1 ml of binding buffer [10 mM HEPES,pH 7.4, 5 mM MgCl₂ and 0.2% bovine serum albumin (BSA)] containing 10 pM¹²⁵I-CGRP and antagonist. After incubation at room temperature for 3 h,the assay was terminated by filtration through GFB glass fibre filterplates (Millipore) that had been blocked with 0.5% polyethyleneimine for3 h. The filters were washed three times with ice-cold assay buffer,then the plates were air dried. Scintillation fluid (50 □l) was addedand the radioactivity was counted on a Topcount (Packard Instrument).Data analysis was carried out by using Prism and the K_(i) wasdetermined by using the Cheng-Prusoff equation (Cheng & Prusoff (1973)Biochein. Pharmacol. 22, 3099-3108).

NATIVE RECEPTOR FUNCTIONAL ASSAY: SK—N-MC cells were grown in minimalessential medium (MEM) supplemented with 10% fetal bovine serum, 2 mML-glutamine, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate, 100units/ml penicillin and 100 □g/ml streptomycin at 37° C., 95% humidity,and 5% CO₂. For cAMP assays, cells were plated at 5×10⁵ cells/well in96-well poly-D-lysine-coated plates (Becton-Dickinson) and cultured for˜18 h before assay. Cells were washed with phosphate-buffered saline(PBS, Sigma) then pre-incubated with 300 □M isobutylmethylxanthine inserum-free MEM for 30 min at 37° C. Antagonist was added and the cellswere incubated for 10 min before the addition of CGRP. The incubationwas continued for another 15 min, then the cells were washed with PBSand processed for cAMP determination according to the manufacturer'srecommended protocol. Maximal stimulation over basal was defined byusing 100 nM CGRP. Dose-response curves were generated by using Prism.Dose-ratios (DR) were calculated and used to construct full Schild plots(Arunlakshana & Schild (1959) Br. J. Pharmacol. 14, 48-58).

RECOMBINANT RECEPTOR: Human CRLR (Genbank accession number L76380) wassubcloned into the expression vector pIREShyg2 (BD Biosciences Clontech)as a 5′NheI and 3′ PmeI fragment. Human RAMP1 (Genbank accession numberAJ001014) was subcloned into the expression vector pMSpuro2 (BDBiosciences Clontech) as a 5′NheI and 3′NotI fragment. 293 cells (humanembryonic kidney cells; ATCC #CRL-1573) were cultured in DMEM with 4.5g/L glucose, 1 mM sodium pyruvate and 2 mM glutamine supplemented with10% fetal bovine serum (FBS), 100 units/mL penicillin and 100 ug/mlstreptomycin, and maintained at 37° C. and 95% humidity. Cells weresubcultured by treatment with 0.25% trypsin with 0.1% EDTA in BBSS.Stable cell line generation was accomplished by co-transfecting 10 ug ofDNA with 30 ug Lipofectamine 2000 (Invitrogen) in 75 cm² flasks. CRLRand RAMP1 expression constructs were co-transfected in equal amounts.Twenty-four hours after transfection the cells were diluted andselective medium (growth medium+300 ug/ml hygromycin and 1 ug/mlpuromycin) was added the following day. A clonal cell line was generatedby single cell deposition utilizing a FACS Vantage SE (BectonDickinson). Growth medium was adjusted to 150 ug/ml hygromycin and 0.5ug/ml puromycin for cell propagation.

RECOMBINANT RECEPTOR BINDING ASSAY: Cells expressing recombinant humanCRLR/RAMP1 were washed with PBS and harvested in harvest buffercontaining 50 mM HEPES, 1 mM EDTA and Complete protease inhibitors(Roche). The cell suspension was disrupted with a laboratory homogenizerand centrifuged at 48,000 g to isolate membranes. The pellets wereresuspended in harvest buffer plus 250 mM sucrose and stored at −70° C.For binding assays, 10 ug of membranes were incubated in 1 ml bindingbuffer (10 mM HEPES, pH 7.4, 5 mM MgCl₂, and 0.2% BSA) for 3 hours atroom temperature containing 10 pM ¹²⁵I-hCGRP (Amersham Biosciences) andantagonist. The assay was terminated by filtration through 96-well GFBglass fiber filter plates (Millipore) that had been blocked with 0.05%polyethyleneimine. The filters were washed 3 times with ice-cold assaybuffer (10 mM HEPES, pH 7:4). Scintillation fluid was added and theplates were counted on a Topcount (Packard). Non-specific binding wasdetermined and the data analysis was carried out with the apparentdissociation constant (K_(i)) determined by using a non-linear leastsquares fitting the bound CPM data to the equation below:

$Y_{\underset{\_}{obsd}} = \frac{\begin{matrix}{{\left( {Y_{\max} - Y_{\min}} \right)\left( {{\% I_{Max}} - {\%_{I\;\min}/100}} \right)} +} \\{Y_{\min} + {\left( {Y_{\max} - Y_{\min}} \right)\left( {100 - {\%\;{I_{\max}/100}}} \right)}}\end{matrix}}{1 + \left( {\lbrack{Drug}\rbrack/{K_{i}\left( {{+ \lbrack{Radiolabel}\rbrack}/K_{d}} \right)}^{nH}} \right.}$Where Y is observed CPM bound, Y_(max) is total bound counts, Y min isnon specific bound counts, (Y max−Y min) is specific bound counts, % Imax is the maximum percent inhibition, % 1 min is the minimum percentinhibition, radiolabel is the probe, and the K_(d) is the apparentdissociation constant for the radioligand for the receptor as determinedby Hot saturation experiments.

RECOMBINANT RECEPTOR FUNCTIONAL ASSAY: Cells were plated in completegrowth medium at 85,000 cells/well in 96-well poly-D-lysine coatedplates (Corning) and cultured for ˜19 h before assay. Cells were washedwith PBS and then incubated with inhibitor for 30 min at 37° C. and 95%humidity in Cellgro Complete Serum-Free/Low-Protein medium (Mediatech,Inc.) with L-glutamine and 1 g/L BSA. Isobutyl-methylxanthine was addedto the cells at a concentration of 3000□M and incubated for 30 min at37° C. Human □-CGRP was added to the cells at a concentration of 0.3 nMand allowed to incubate at 37° C. for 5 min. After □-CGRP stimulationthe cells were washed with PBS and processed for cAMP determinationutilizing the two-stage assay procedure according to the manufacturer'srecommended protocol (cAMP SPA direct screening assay system; RPA 559;Amersham Biosciences). Dose response curves were plotted and IC₅₀ valuesdetermined from a 4-parameter logistic fit as defined by the equationy=((a−d)/(1+(x/c)^(b))+d, where y=response, x=dose, a=max response,d=min response, c=inflection point and b=slope.

In particular, the compounds of the following examples had activity asantagonists of the CGRP receptor in the aforementioned assays, generallywith a K_(i) or IC₅₀ value of less than about 50 □M. Such a result isindicative of the intrinsic activity of the compounds in use asantagonists of CGRP receptors.

The ability of the compounds of the present invention to act as CGRPantagonists makes them useful pharmacological agents for disorders thatinvolve CGRP in humans and animals, but particularly in humans.

The compounds of the present invention have utility in treating,preventing, ameliorating, controlling or reducing the risk of one ormore of the following conditions or diseases: headache; migraine;cluster headache; chronic tension type headache; pain; chronic pain;neurogenic inflammation and inflammatory pain; neuropathic pain; eyepain; tooth pain; diabetes; non-insulin dependent diabetes mellitus;vascular disorders; inflammation; arthritis; bronchial hyperreactivity,asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance;hot flashes in men and women; allergic dermatitis; psoriasis;encephalitis; brain trauma; epilepsy; neurodegenerative diseases; skindiseases; neurogenic cutaneous redness, skin rosaceousness and erythema;inflammatory bowel disease, irritable bowel syndrome, cystitis; andother conditions that may be treated or prevented by antagonism of CGRPreceptors. Of particular importance is the acute or prophylactictreatment of headache, including migraine and cluster headache.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of the diseases,disorders and conditions noted herein.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of theaforementioned diseases, disorders and conditions in combination withother agents.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of Formula I or the other drugs may have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Such other drug(s) may be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of Formula I. When a compound of Formula Iis used contemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of Formula I is preferred. However, the combination therapy mayalso include therapies in which the compound of Formula I and one ormore other drugs are administered on different overlapping schedules. Itis also contemplated that when used in combination with one or moreother active ingredients, the compounds of the present invention and theother active ingredients may be used in lower doses than when each isused singly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of Formula I.

For example, the present compounds may be used in conjunction with an ananti-migraine agent, such as ergotamine and dihydroergotamine, or otherserotonin agonists, especially a 5-HT_(1B/1D) agonist, for examplesumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan,frovatriptan, donitriptan, and rizatriptan, a 5-HT_(1D) agonist such asPNU-142633 and a 5-HT_(1F) agonist such as LY334370; a cyclooxygenaseinhibitor, such as a selective cyclooxygenase-2 inhibitor, for examplerofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib; anon-steroidal anti-inflammatory agent or a cytokine-suppressinganti-inflammatory agent, for example with a compound such as ibuprofen,ketoprofen, fenoprofen, naproxen, indomethacin, sulindac, meloxicam,piroxicam, tenoxicam, lornoxicam, ketorolac, etodolac, mefenamic acid,meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac,oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanercept,tolmetin, phenylbutazone, oxyphenbutazone, diflunisal, salsalate,olsalazine or sulfasalazine and the like; or glucocorticoids. Similarly,the instant compounds may be administered with an analgesic such asaspirin, acetaminophen, phenacetin, fentanyl, sufentanil, methadone,acetyl methadol, buprenorphine or morphine.

Additionally, the present compounds may be used in conjunction with aninterleukin inhibitor, such as an interleukin-1 inhibitor; an NK-1receptor antagonist, for example aprepitant; an NMDA antagonist; an NR2Bantagonist; a bradykinin-1 receptor antagonist; an adenosine A1 receptoragonist; a sodium channel blocker, for example lamotrigine; an opiateagonist such as levomethadyl acetate or methadyl acetate; a lipoxygenaseinhibitor, such as an inhibitor of 5-lipoxygenase; an alpha receptorantagonist, for example indoramin; an alpha receptor agonist; avanilloid receptor antagonist; a renin inhibitor; a granzyme Binhibitor; a substance P antagonist; an endothelin antagonist; anorepinephrin precursor; anti-anxiety agents such as diazepam,alprazolam, chlordiazepoxide and chlorazepate; serotonin 5HT₂ receptorantagonists; opiod agonists such as codeine, hydrocodone, tramadol,dextropropoxyphene and febtanyl; an mGluR5 agonist, antagonist orpotentiator; a GABA A receptor modulator, for example acamprosatecalcium; nicotinic antagonists or agonists including nicotine;muscarinic agonists or antagonists; a selective serotonin reuptakeinhibitor, for example fluoxetine, paroxetine, sertraline, duloxetine,escitalopram, or citalopram; an antidepressant, for exampleamitriptyline, nortriptyline, clomipramine, imipramine, venlafaxine,doxepin, protriptyline, desipramine, trimipramine, or imipramine; aleukotriene antagonist, for example montelukast or zafirlukast; aninhibitor of nitric oxide or an inhibitor of the synthesis of nitricoxide.

Also, the present compounds may be used in conjunction with gap junctioninhibitors; neuronal calcium channel blockers such as civamide; AMPA/KAantagonists such as LY293558; sigma receptor agonists; and vitamin B2.

Also, the present compounds may be used in conjunction with ergotalkaloids other than ergotamine and dihydroergotamine, for exampleergonovine, ergonovine, methylergonovine, metergoline, ergoloidmesylates, dihydroergocomine, dihydroergocristine, dihydroergocryptine,dihydro-α-ergocryptine, dihydro-β-ergocryptine, ergotoxine, ergocornine,ergocristine, ergocryptine, α-ergocryptine, β-ergocryptine, ergosine,ergostane, bromocriptine, or methysergide.

Additionally, the present compounds may be used in conjunction with abeta-adrenergic antagonist such as timolol, propanolol, atenolol,metoprolol or nadolol, and the like; a MAO inhibitor, for examplephenelzine; a calcium channel blocker, for example flunarizine,diltiazem, amlodipine, felodipine, nisolipine, isradipine, nimodipine,lomerizine, verapamil, nifedipine, or prochlorperazine; neurolepticssuch as olanzapine, droperidol, prochliorperazine, chlorpromazine andquetiapine; an anticonvulsant such as topiramate, zonisamide,tonabersat, carabersat, levetiracetam, lamotrigine, tiagabine,gabapentin, pregabalin or divalproex sodium; an anti-hypertensive suchas an angiotensin II antagonist, for example losartan, irbesartin,valsartan, eprosartan, telmisartan, olmesartan, medoxomil, candesartanand candesartan cilexetil, an angiotensin I antagonist, an angiotensinconverting enzyme inhibitor such as lisinopril, enalapril, captopril,benazepril, quinapril, perindopril, ramipril and trandolapril; orbotulinum toxin type A or B.

The present compounds may be used in conjunction with a potentiator suchas caffeine, an H2-antagonist, simethicone, aluminum or magnesiumhydroxide; a decongestant such as oxymetazoline, epinephrine,naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine;an antitussive such as caramiphen, carbetapentane, or dextromethorphan;a diuretic; a prokinetic agent such as metoclopramide or domperidone; asedating or non-sedating antihistamine such as acrivastine, azatadine,bromodiphenhydramine, brompheniramine, carbinoxamine, chlorpheniramine,clemastine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine,doxylamine, loratadine, phenindamine, pheniramine, phenyltoloxamine,promethazine, pyrilamine, terfenadine, triprolidine, phenylephrine,phenylpropanolamine, or pseudoephedrine. The present compounds also maybe used in conjunction with anti-emetics.

In a particularly preferred embodiment the present compounds are used inconjunction with an anti-migraine agent, such as: ergotamine ordihydroergotamine; a 5-HT₁ agonist, especially a 5-HT_(1B/1D) agonist,in particular, sumatriptan, naratriptan, zolmitriptan, eletriptan,almotriptan, frovatriptan, donitriptan, avitriptan and rizatriptan, andother serotonin agonists; and a cyclooxygenase inhibitor, such as aselective cyclooxygenase-2 inhibitor, in particular, rofecoxib,etoricoxib, celecoxib, valdecoxib or paracoxib.

The above combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds. Likewise, compounds of the presentinvention may be used in combination with other drugs that are used inthe prevention, treatment, control, amelioration, or reduction of riskof the diseases or conditions for which compounds of the presentinvention are useful. Such other drugs may be administered, by a routeand in an amount commonly used therefore, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition containing such other drugs inaddition to the compound of the present invention is preferred.Accordingly, the pharmaceutical compositions of the present inventioninclude those that also contain one or more other active ingredients, inaddition to a compound of the present invention.

The weight ratio of the compound of the present invention to the otheractive ingredient(s) may be varied and will depend upon the effectivedose of each ingredient. Generally, an effective dose of each will beused. Thus, for example, when a compound of the present invention iscombined with another agent, the weight ratio of the compound of thepresent invention to the other agent will generally range from about1000:1 to about 1:1000, or from about 200:1 to about 1:200. Combinationsof a compound of the present invention and other active ingredients willgenerally also be within the aforementioned range, but in each case, aneffective dose of each active ingredient should be used.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s), and via thesame or different routes of administration.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active compound is included in anamount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, solutions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia; and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in the U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlrelease. Oral tablets may also be formulated for immediate release, suchas fast melt tablets or wafers, rapid dissolve tablets or fast dissolvefilms.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention are employed.Similarly, transdermal patches may also be used for topicaladministration.

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

In the treatment, prevention, control, amelioration, or reduction ofrisk of conditions which require antagonism of CGRP receptor activity anappropriate dosage level will generally be about 0.01 to 500 mg per kgpatient body weight per day which can be administered in single ormultiple doses. A suitable dosage level may be about 0.01 to 250 mg/kgper day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg perday. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to50 mg/kg per day. For oral administration, the compositions are may beprovided in the form of tablets containing 1.0 to 1000 milligrams of theactive ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0,75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0,800.0, 900.0, and 1000.0 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds may be administered on a regimen of 1 to 4 times per day, ormay be administered once or twice per day.

When treating, preventing, controlling, ameliorating, or reducing therisk of headache, migraine, cluster headache, or other diseases forwhich compounds of the present invention are indicated, generallysatisfactory results are obtained when the compounds of the presentinvention are administered at a daily dosage of from about 0.1 milligramto about 100 milligram per kilogram of animal body weight, given as asingle daily dose or in divided doses two to six times a day, or insustained release form. For most large mammals, the total daily dosageis from about 1.0 milligrams to about 1000 milligrams, or from about 1milligrams to about 50 milligrams. In the case of a 70 kg adult human,the total daily dose will generally be from about 7 milligrams to about350 milligrams. This dosage regimen may be adjusted to provide theoptimal therapeutic response.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare made according to procedures known in the art or as illustratedherein.

The compounds of the present invention can be prepared readily accordingto the following Schemes and specific examples, or modificationsthereof, using readily available starting materials, reagents andconventional synthesis procedures. In these reactions, it is alsopossible to make use of variants which are themselves known to those ofordinary skill in this art but are not mentioned in greater detail. Thegeneral procedures for making the compounds claimed in this inventioncan be readily understood and appreciated by one skilled in the art fromviewing the following Schemes.

The synthesis of aniline intermediates may be conducted as described inSchemes 1-5. Aniline intermediates bearing R^(5a), R^(5b) and R^(5c) maybe prepared by employing appropriately substituted starting materials orby derivatization of any intermediates and/or final products as desiredby methods known in the art.

The synthesis of a representative spirolactam aniline (6) is illustratedin Scheme 1. The known ethyl indane-2-carboxylate (1, Schaaf et al., J.Med. Chem. 1983, 26, 328-334) may be alkylated with allyl bromide andsodium bis(trimethylsilyl)amide to form 2. Oxidation of the allyl groupwith ozone can produce the aldehyde 3, which cyclizes to the lactam 4after treatment with ammonium acetate and sodium cyanoborohydride andheating in toluene. The reductive amination of aldehyde 3 with aminesother than ammonia may be used to provide a variety of N-protectedanalogues of lactam 4, which may facilitate subsequent chemical stepsprior to removal of the lactam protecting group. The intermediate lactammay be nitrated, for example using 70% nitric acid, and the resultingnitro compound 5 can be reduced to provide the aniline intermediate 6,using a variety of well known methodologies, such as catalytichydrogenation. Those skilled in the art of organic synthesis willrecognize that straightforward modifications of this methodology may beused to access other spirolactam intermediates, such as those with otherlactam ring sizes. Additionally, use of an alternative starting materialto the indane 1 may be used to provide different products, such astetralin-based spirolactams.

In Scheme 2, an example of the synthesis of a spirooxindole intermediateis shown. Treatment of oxindole (7) with butyllithium andtetramethylethylenediamine, followed by a dihalide or its equivalent,e.g. 4-bromo-1,2-bis(bromomethyl)benzene [Anderson et al., J. Org. Chem.1979, 44(9), 1519-1533], leads to the spirooxindole 9. The bromide maybe converted to a carboxylic acid (10) by treatment with ethylmagnesiumbromide and tert-butyllithium, and quenching of the resultingorganolithium species with carbon dioxide. A Curtius rearrangement usingdiphenylphosphoryl azide in tert-butanol, followed by deprotection withhydrochloric acid can provide the aniline 11. Alternative conditions,such as treatment of acid 10 with sodium azide in concentrated sulfuricacid, may also be used to provide aniline 11.

Scheme 3 illustrates a route to spiroimide derivative 16, usingmethodology that is similar to that shown in Scheme 1. Ethylindane-2-carboxylate (1) may be alkylated with tert-butyl bromoacetateto form the diester 12. Subjection of 12 to basic, then acidichydrolysis conditions can provide the diacid 13. Treatment of the diacid13 with a number of different reagents can provide imide 14 or aderivative thereof. In Scheme 3, heating 13 in the presence of acetylchloride, followed by reaction with ammonia affords spiroimide 14.Reaction with sodium nitrite in trifluoroacetic acid, followed byhydrogenation over palladium can provide the aniline 16.

A representative synthesis of a spiroazaoxindole intermediate is shownin Scheme 4. 7-Azaindole (17) may be protected with a variety ofprotecting groups, such as the (trimethylsilyl)ethoxymethyl group shownin Scheme 4. Following the method of Marfat and Carter (TetrahedionLett., 1987, 28, 4027-4030), treatment of 18 with pyridine hydrobromideperbromide provides the dibromoazaoxindole 19, which may be reduced tothe corresponding azaoxindole 20 by reaction with zinc. The keyalkylation of 20 with 1,2-bis(bromomethyl)-4-nitrobenzene (21, Cava etal., J. Org. Chem. 2000, 65, 5413-5415) is carried out using cesiumcarbonate in DMF to afford the spiroazaoxindole 22. A variety of otherbases and solvents may be employed in this alkylation reaction, and useof an alternative alkylating agent to the dibromide shown here can leadto different products. Reduction of the nitro compound 22, for exampleusing hydrogenation over palladium, and a two-step deprotection affordsthe corresponding aniline 24. The methodology shown in Scheme 4 is notlimited to azaoxindoles such as 20, but may be applied to a variety ofsuitably protected heterocyclic systems to give the corresponding spirocompounds.

Spiroazaoxindole intermediates, such as those illustrated in Scheme 4,may be resolved to give pure enantiomers using techniques familiar tothose skilled in the art. For example, chromatography of the protectedintermediate 23 on a ChiralPak OD column can be used to provide theindividual enantiomers (+)-23 and (−)-23, and these enantiomers may beconverted to the corresponding anilines [(+)-24 and (−)-24] by thetwo-step deprotection. In the case of compound 24, the dextro isomer isthe (R)-enantiomer and the levo isomer (S)-enantiomer, i.e. (+)-24 is(R)-24 and (−)-24 is (S)-24. Use of standard coupling procedures usingenantiomerically pure anilines can provide the individual enantiomers ofthe final products. Resolution may be effected by other methodologies,such as fractional crystallization of diastereomeric salts, and it maybe carried out on other synthetic intermediates or on the finalproducts. Alternatively, an asymmetric synthesis of a key intermediatecould be used to provide an enantiomerically enriched final product.

As an example of related methodology to that described in Scheme 4,using alternative conditions for the alkylation reaction, the synthesisof spirodiazaoxindole compounds is outlined in Scheme 5. Publishedmethodology is used to convert 6-chloro-deazapurine into4-chloro-diazaoxindole 25, the starting material in Scheme 5 (Sun etal., Biorg Med. Chem Lett. 2002, 12, 2153-2157).

Alkylation with dibromide 21 under similar conditions to that shown inScheme 2 may provide the spirodiazaoxindole 26. Hydrogenation at 30 psifor two hours can provide the aniline 27, while hydrogenation at higherpressure (55 psi) and longer reaction time (180 hours) can provide thedes-chloroanalogue 28.

Aniline intermediates, such as those described in Schemes 1-5, may becoupled with a variety of carboxylic acids, or carboxylic acidderivatives, to provide amide final products.

Thus, coupling of amine A with a carboxylic acid, R′CO₂H, can be used togive amide B. Other standard coupling conditions may be employed in thesynthesis of such amides, such as use of an alternative coupling reagentlike PyBOP, or activation of the carboxylic acid as an acid anhydride oracid chloride. Ureas may also be synthesized from aniline A and anappropriate amine by use of phosgene, 1,1′-carbonyldiimidazole,4-nitrophenyl chloroformate, or a similar reagent.

Most of the acids (R′CO₂H), used to make the compounds of the presentinvention are readily available. They may be obtained from commercialsources or synthesized by methodology familiar to those skilled in theart and as described in the chemical literature. A number of the acidswere synthesized using the methodology outlined in Schemes 7-14.

In Scheme 7, carbonylation of a 2-aminophenol (C) with1,1′-carbonyldiimidazole affords the benzoxazolone D, which is treatedwith sodium hydride, then tert-butyl bromoacetate, to provide ester E.Standard deprotection using trifluoroacetic acid affords the acidintermediate F, which may be used for coupling to amines like A to givecompounds of the present invention.

Scheme 8 illustrates a general route to substituted benzimidazolonederivatives. Simple alkylation of the benzimidazolone G affords theacetate derivative H, which may be separated from any bis-alkylatedmaterial by chromatography. For a variety of aryl or heteroaryl R₁,reaction of the corresponding bromide (R₁Br) with H using coppercatalysis provides the N,N-disubstituted intermediate I. The tert-butylester I may be deprotected under acidic conditions to give J, which isreadily converted to the final products. The chemistry in Scheme 8 maybe modified in a number of ways. For example, use of alternativeconditions for the key transformation of H to I can permit a variety ofR₁ substituents to be introduced. Examples of such alternativeconditions include a palladium-catalyzed coupling with H, or analkylation or arylation of the anion of H under basic conditions, forexample using sodium hydride followed by R₁Cl. Further chemicalmanipulation of the substituents R₁ and R₂ is also understood to bewithin the scope of this invention. Either R₁ or R₂ may be modifiedunder a variety of conditions at one or more intermediate steps in thesynthetic sequence to afford a diverse group of final products. Anexample of this strategy is shown in Scheme 9.

In Scheme 9, benzimidazolone G is reacted with 2,4-dibromothiazole togive bromothiazole K. Displacement of the bromide in K withthiomethoxide affords intermediate L, which may be alkylated to giveester M in analogy with other schemes shown herein. Subjection of M tooxidative conditions, such as use of OXONE®, can provide thecorresponding sulfoxide, which may be deprotected to give acid N. Slightmodifications of these conditions could be applied to afford thecorresponding sulfide or sulfoxide analogues.

In Scheme 10, another route to the substituted benzimidazolone J isshown. In this route, an amine (R₁NH₂) is condensed with a2-chloronitroarene derivative (P) to give amine Q. The nitro group maybe reduced, for example under catalytic hydrogenation conditions, togive the corresponding aniline, and this may be treated with triphosgeneto afford the benzimidazolone R. Elaboration of R in analogy with theearlier Schemes leads to the desired acid intermediate J. In a simplevariation of this methodology, the arene P may be replaced with aheterocycle, such as 2-chloro-3-nitropyridine to afford an aza analogueof J.

In Scheme 11, a route to regiospecifically-substituted benzimidazoloneintermediate H from the corresponding anthranilic acid is shown.Treatment of the anthranilic acid T with phosgene can lead to thebenzoxazinedione U. Alkylation of U with tert-butyl bromoacetate,followed by opening of the benzoxazinedione ring with NaOH, provides thealkylated anthranilic acid V. Treatment of acid V withdiphenylphosphoryl azide leads to a Curtius rearrangement in which theintermediate isocyanate is trapped to give the benzimidazolone H. Thisroute offers a method of installing the R₂ substituent(s) in positionsdictated by the substitution pattern of the anthranilic acid startingmaterial.

A synthesis of N-spirooxindole acetic acids is outlined in Scheme 12.Following chemistry described in U.S. Pat. No. 5,849,780 A (1998), anexample of such begins with the alkylation of oxindole (W) with a halideor its equivalent, e.g. 2-(2-bromoethoxy)tetrahydro-2H-pyran, and abase, such as potassium tert-butoxide or butyllithium, to yieldintermediate X. Treatment with bromine produces the tribromide Y, whichwhen reacted with sodium sulfide can give the spirooxindole Z.Alternatively, W could be alkylated with a dihalide or otherbis-alkyating agent, e.g. 2-iodoethyl ether, to produce a spirooxindoledirectly. Alkylation of oxindole Z with ethyl bromoacetate followed byhydrolysis affords the desired acid intermediate BB. Further chemicalmanipulation of substituents on the aryl ring is understood to be withinthe scope of this invention. An example of this strategy is shown in thelast step when the bromide is removed by treatment with ethylmagnesiumbromide and tert-butyllithium to produce carboxylic acid CC.

Another method for synthesizing spiroxoindoles is outlined in Scheme 13,in which W is initially trialkylated with methyl acrylate according tochemistry described in U.S. Pat. No. 6,573,386 B1 (2001). In the samereaction flask, the intermediate then undergoes a Dieckmanncondensation, N-dealkylation, and decarboxylation to producespirocyclohexanone DD. Further manipulation as described in previousschemes may be used to produce carboxylic acid intermediates like FF.

Scheme 14 illustrates a general route to substituted indole aceticacids. Substituted indoles (GG) can be converted to indole acetonitriles(II) via a two step sequence: alkylation withN,N,N′,N′-tetramethylmethanediamine followed by displacement withpotassium cyanide. Alternatively, the first intermediate (HH) can beformed by reaction of indole GG with dimethylamine and formaldehyde in amicrowave reactor. Treatment with hydrochloric acid in methanol canconvert the nitrile to the methyl ester JJ. Further manipulation inanalogy with previous schemes can produce carboxylic acid intermediateslike LL. Azaindole acetic acids may also be synthesized via a similarscheme starting with an appropriately substituted azaindole.

Simple modifications of these routes, including different protectinggroup strategies, application of well-precedented methodology, and theuse of heterocycles and reagents other than those described in theforegoing Schemes, may be used to provide other acids of interest, suchas those detailed in Intermediates 24-36 (vide infra).

In some cases the final product may be further modified, for example, bymanipulation of substituents. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart.

In some cases the order of carrying out the foregoing reaction schemesmay be varied to facilitate the reaction or to avoid unwanted reactionproducts. The following examples are provided so that the inventionmight be more fully understood. These examples are illustrative only andshould not be construed as limiting the invention in any way.

INTERMEDIATE 1

(±)-5-Amino-1,3-dihydro-2′H-spiro[indene-2,3′-pyrrolidin]-2′-one

Step A. Ethyl 2-allylindane-2-carboxylate

To a solution of ethyl indane-2-carboxylate [Schaaf et al., J. Med.Chem. 1983, 26, 328-334] (6.87 g, 36.1 mmol) in THF (100 mL) at −78° C.was added sodium his(trimethylsilyl)amide (1.0 M in THF, 39.7 mL, 39.7mmol) drop wise over 20 min. The resulting yellow solution was stirredfor 1 h, and then allyl bromide (3.75 mL, 43.3 mmol) was added over 5minutes. Stirring was continued for 1.5 h at −78° C., and then thereaction was quenched by the addition of saturated NH₄Cl (50 mL) andwarmed to ambient temperature. The reaction mixture was partitionedbetween saturated NH₄Cl (100 mL) and EtOAc (100 mL). The aqueous phasewas further extracted with EtOAc (2×50 mL), and the combined organiclayers were dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The crude product was purified by silica gel chromatography,eluting with a gradient of hexane:EtOAc-100:0 to 75:25, to give thetitle compound. MS: m/z=231 (M+1).

Step B. Ethyl 2-(2-oxoethyl)indane-2-carboxylate

Ethyl 2-allylindane-2-carboxylate from Step A (3.00 g, 13.0 mmol) wasdissolved in CH₂Cl₂ (100 mL) and cooled to −78° C. Ozone was bubbledthrough the solution for 15 minutes, at which time a light blue colorpersisted. Triethylamine (3.63 mL, 26.1 mmol) was added and the reactionmixture was stirred at ambient temperature for 1.5 h. The reactionmixture was partitioned between saturated NaHCO₃ (100 mL) and CH₂Cl₂(100 mL). The aqueous phase was further extracted with CH₂Cl₂ (2×50 mL),and the combined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to give the title compound. MS:m/z=233 (M+1).

Step C. 1,3-Dihydro-2′H-spiro[indene-23′-pyrrolidin]-2′-one

Ethyl 2-(2-oxoethyl)indane-2-carboxylate from Step B (3.03 g, 13.0 mmol)and ammonium acetate (50.2 g, 651 mmol) were stirred in AcOH (20 mL) andMeOH (20 mL) at ambient temperature for 4 h, then sodiumcyanoborohydride (1.29 g, 19.5 mmol) was added and stirring continuedfor 16 h. The reaction mixture was concentrated in vacuo and partitionedbetween saturated NaHCO₃ (50 mL) and CH₂Cl₂ (50 mL). The aqueous phasewas further extracted with CH₂Cl₂ (2×25 mL), and the combined organiclayers were dried over Na₂SO₄, filtered, and concentrated under reducedpressure to yield a yellow oil. The crude oil was heated to reflux intoluene (100 mL) for 1.5 h and then concentrated in vacuo. The crudeproduct was purified by silica gel chromatography, eluting with agradient of CH₂Cl₂:MeOH-100:0 to 90:10, to give the title compound. MS:m/z=188 (M+1).

Step D. (±)-5-Nitro-1,3-dihydro-2′H-spiro[indene-2,3′-pyrrolidin]-2′-one

To 1,3-dihydro-2′H-spiro[indene-2,3′-pyrrolidin]-2′-one from Step C (114mg, 0.609 mmol) cooled in an ice bath was added 70% HNO₃ (5 mL). Thereaction mixture was stirred for 45 min, diluted with H₂O (10 mL), andextracted with CH₂Cl₂ (3×10 mL). The combined organic layers were driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Thecrude product was purified by silica gel chromatography, eluting with agradient of CH₂Cl₂:EtOAc-100:0 to 50:50, to give the title compound. MS:m/z=233 (M+1).

Step E. (±)-5-Amino-1,3-dihydro-2′H-spiro[indene-23′-pyrrolidin]-2′-one

To a solution of(±)-5-nitro-1,3-dihydro-2′H-spiro[indene-2,3′-pyrrolidin]-2′-one fromStep D (97.0 mg, 0.418 mmol) in MeOH(5 mL) was added 10% Pd/C (15 mg).The reaction mixture was stirred under a hydrogen atmosphere (ca. 1 atm)for 1.5 h, then filtered through a Celite pad and concentrated underreduced pressure to give the title compound. MS: m/z=203 (M+1).

INTERMEDIATE 2

(±)-5-Amino-1,3-dihydrospiro[indene-2,3′-indol]-2′(1′H)-one

Step A. (±)-5-Bromo-1,3-dihydrospiro[indene-2,3′-indol]-2′(1′H)-one

To a solution of oxindole (363 mg, 2.73 mmol) at −78° C. in THF (15 mL)was added butyllithium (2.5 M in hexanes, 2.29 mL, 5.73 mmol) drop wise,followed by the drop wise addition of tetramethylethylenediamine (0.905mL, 6.00 mmol). The solution was stirred for 1 h at −78° C., then asolution of 4-bromo-1,2-bis(bromomethyl)benzene [Anderson et al., J.Org. Chem. 1979, 44(9), 1519-1533] (1.87 g, 5.45 mmol) in THF (5 mL) wasadded drop wise. The reaction solution was stirred at −10 to −20° C. for2 h and at ambient temperature for 16 h. The reaction mixture waspartitioned between saturated NH₄Cl (50 mL) and EtOAc (50 mL). Theaqueous phase was further extracted with EtOAc (2×50 mL), and thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude product was purified bysilica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0to 50:50, to give the title compound. MS: m/z=315 (M+1).

Step B.(±)-2′-Oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3°-indole]-5-carboxylicacid

To a solution of(±)-5-bromo-1,3-dihydrospiro[indene-2,3′-indol]-2′(1′H)-one from Step A(220 mg, 0.700 mmol) in THF (2 mL) was added ethylmagnesium bromide (3.0M in ether, 0.467 mL, 1.40 mmol) drop wise, maintaining the reactiontemperature <−60° C. Then tert-butyllithium (1.7 M in pentane, 1.65 mL,2.80 mmol) was added drop wise, maintaining the reaction temperature<−60° C. The reaction solution was stirred for 5 min at −78° C., thenCO₂(g) was bubbled through the solution for 15 min. H₂O (5 mL) was addedand the solution was warmed to ambient temperature. The reaction mixturewas partitioned between EtOAc (20 mL) and saturated NaHCO₃ (20 mL). Theorganic layer was further extracted with saturated NaHCO₃ (2×10 mL). Thecombined aqueous layers were washed with EtOAc (10 mL) and thenacidified with 12M HCl. The combined aqueous layers were extracted withCH₂Cl₂ (5×10 mL). A white precipitate formed that was insoluble ineither layer, and was collected by filtration. The combined CH₂Cl₂layers were dried over Na₂SO₄, filtered, and concentrated under reducedpressure. This crude product was combined with the recovered precipitateto give the title compound. MS: m/z=280 (M+1).

Step C. (±)-tert-Butyl(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-indol]-5-yl)carbamate

A solution of(±)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-indole]-5-carboxylicacid from Step B (65.0 mg, 0.233 mmol), diphenylphosphoryl azide (0.060mL, 0.279 mmol), and triethylamine (0.039 mL, 0.279 mmol) in t-BuOH (5mL) was heated to reflux for 3 h. The reaction mixture was concentratedin vacuo. The crude product was purified by silica gel chromatography,eluting with a gradient of hexane:EtOAc-100:0 to 50:50, to give thetitle compound. MS: m/z=295 (M-C₄H₇).

Step D. (±)-5-Amino-1,3-dihydrospiro[indene-2,3′-indol]-2′(1′H)-one

HCl(g) was bubbled through a solution of (±)-tert-butyl(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-indol]-5-yl)carbamate fromStep C (19.0 mg, 0.054 mmol) in EtOAc (5 mL) for 15 min. The reactionmixture was stirred at ambient temperature for 1 h and then concentratedin vacuo to give the title compound as the hydrochloride salt. MS:m/z=251 (M+1).

INTERMEDIATE 3

(±)-5-Amino-1,3-dihydro-2′H,5′H-spiro[indene-2,3′-pyrrolidine]-2′,5′-dione

Step A. Ethyl 2-(2-tert-butoxy-2-oxoethyl)indane-2-carboxylate

To a solution of ethyl indane-2-carboxylate [Schaaf et al., J. Med.Chem. 1983, 26, 328-334] (2.00 g, 10.5 mmol) in TIE at −78° C. was addedsodium bis(trimethylsilyl)amide (15.8 mL of a 1.0 M solution in THF,15.8 mmol) drop wise over 10 min. The mixture was stirred for 15 min,then tert-butyl bromoacetate (3.08 g, 15.8 mmol) was added drop wiseover 30 min. The resulting mixture was stirred for 30 min at −78° C.,then poured into brine (20 mL) and extracted with EtOAc (50 mL). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated invacuo. The crude product was purified by silica gel chromatography,eluting with a gradient of hexane:EtOAc-100:0 to 90:10, to give thetitle compound. MS: m/z=368 (M+Na+CH₃CN).

Step B. 2-(2-tert-Butoxy-2-oxoethyl)indane-2-carboxylic acid

A mixture of ethyl 2-(2-tert-butoxy-2-oxoethyl)indane-2-carboxylate fromStep A (2.48 g, 8.15 mmol) and 1.0 N sodium hydroxide (8.96 mL, 8.96mmol) in THF (50 mL), H₂O (10 mL), and EtOH (20 mL) was stirred atambient temperature for 18 h. The mixture was acidified withhydrochloric acid to about pH 3 and extracted with EtOAc (3×50 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo to give the title compound. MS: m/z=340(M+Na+CH₃CN).

Step C. (Carboxymethyl)indane-2-carboxylic acid

A solution of 2-(2-tert-butoxy-2-oxoethyl)indane-2-carboxylic acid fromStep B (1.50 g, 5.43 mmol) in EtOAc (100 mL) was saturated with HCl (g)and aged at ambient temperature for 1 h, then concentrated to dryness invacuo to give the title compound. MS: 7 m/z=284 (M+Na+CH₃CN).

Step D. 1,3-Dihydro-2H,5′H-spiro[indene-2,3′-pyrrolidine]-2′,5′-dione

A solution of 2-(carboxymethyl)indane-2-carboxylic acid from Step C(1.10 g, 4.99 mmol) in acetyl chloride (18 mL) was heated at reflux for18 h, then concentrated in vacuo. The residue was recrystallized fromtoluene to give 1′,3′-dihydrospiro[furan-3,2′-indene]-2,5(4H)-dione asan ivory solid. This solid was dissolved in CH₂Cl₂ (25 mL) and NH₃ (g)was bubbled into the mixture for 20 min. After a further 30 min, thesolvent was evaporated under reduced pressure. The resulting solid wasdried under high vacuum for 1 h, then resuspended in acetyl chloride (20mL) and heated to reflux for 18 h. The solvent was removed in vacuo andthe crude solid was recrystallized from EtOH:Et₂O to afford the titlecompound. MS: m/z=202 (M+1).

Step E.(±)-5-Amino-1,3-dihydro-2′H,5H-spiro[indene-2,3′-pyrrolidine]-2′,5′-dione

To a solution of1,3-dihydro-2′H,5′H-spiro[indene-2,3′-pyrrolidine]-2′,5′-dione from StepD (400 mg, 1.99 mmol) in CF₃CO₂H (10 mL) was added sodium nitrite (411mg, 5.96 mmol) and the mixture was heated to 55° C. for 2 h. The mixturewas cooled and diluted with H₂O (10 mL), then extracted with EtOAc (2×30mL). The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo, to give5-nitro-1,3-dihydro-2′H,5′H-spiro[indene-2,3′-pyrrolidine]-2′,5′-dione,which contained some of the isomeric4-nitro-1,3-dihydro-2′H,5′H-spiro[indene-2,3′-pyrrolidine]-2′,5′-dione.This solid was dissolved in EtOH (30 mL), then AcOH (0.55 mL) and 10%Pd/C (55 mg) were added. The mixture was stirred vigorously under anatmosphere of hydrogen (ca. 1 atm) for 2 h, then filtered through a padof Celite, and concentrated in vacuo. The crude product was purified bysilica gel chromatography, eluting with a gradient of CH₂Cl₂:EtOAc—95:5to 10:90, to give the title compound. MS: m/z=217 (M+1).

INTERMEDIATE 4

(−)-5-Amino-1,3-dihydrospiro[indene-2,3°-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

Step A. 1-{[2-Trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine

Sodium hydride (60% dispersion in mineral oil; 16.2 g, 0.404 mol) wasadded in portions over 25 min to a solution of 7-azaindole (39.8 g,0.337 mol) in DMF (200 mL) at 0 □C and the mixture was stirred for 1 h.2-(Trimethylsilyl)ethoxymethyl chloride (71.8 mL, 0.404 mol) was thenadded slowly over 15 min, keeping the temperature of the reactionmixture below 10 □C. After 1 h, the reaction was quenched with H₂O (500mL) and the mixture was extracted with CH₂Cl₂ (5×300 mL). The combinedorganic layers were washed with brine, dried over MgSO₄, filtered,concentrated, and dried under high vacuum to give the title compound.MS: m/z=249 (M+1).

Step B.3,3-Dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

A solution of1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine from StepA (43.1 g, 0.174 mol) in dioxane (300 mL) was added dropwise over 30 minto a suspension of pyridine hydrobromide perbromide (277 g, 0.868 mol)in dioxane (300 mL). The reaction was stirred at ambient temperatureusing an overhead mechanical stirrer. After 60 min, the biphasicreaction mixture was quenched with H₂O (300 mL) and extracted with EtOAc(300 mL). The aqueous layer was washed with EtOAc (2×300 mL) and thecombined organic layers were washed with H₂O (4×300 mL; the final washwas pH 5-6), then brine (300 mL), then dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude product was immediatelydissolved in CH₂Cl₂ and the solution filtered through a plug of silica,eluting with CH₂Cl₂ until the dark red color had completely eluted fromthe plug. The filtrate was washed with saturated aqueous NaHCO₃ (400mL), then brine (400 mL), dried over MgSO₄ and concentrated in vacuo togive the title compound. MS: m/z=423 (M+1).

Step C.1-{[2-(Trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

Zinc (100 g, 1.54 mol) was added to a solution of3,3-dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-onefrom Step B (65 g, 0.154 mol) in THF (880 mL) and saturated aqueousNH₄Cl (220 mL). After 3 h, the reaction was filtered and concentrated invacuo. The residue was partitioned between EtOAc (500 mL) and H₂O (500mL), which resulted in the formation of a white precipitate. Both layerswere filtered through a Celite pad and the layers were separated. Theaqueous layer was further extracted with EtOAc (2×200 mL) and thecombined organic layers were washed with H₂O (100 mL), dried over MgSO₄,filtered, and concentrated. The crude product was filtered through aplug of silica gel, eluting with EtOAc:CH₂Cl₂-10:90, and the eluant wasconcentrated under reduced pressure to provide the title compound. MS:m/z=265 (M+1).

Step D. (4-Nitro-1,2-phenylene)dimethanol

A solution of 4-nitrophthalic acid (40.0 g, 189.5 mmol) in THF (500 mL)was added drop wise over 1.5 h to a solution of borane-THF complex (1 M,490 mL, 490 mmol), maintaining the reaction temperature between 0 □C and5 □C. After the addition, the reaction was allowed to warm slowly toambient temperature and stirred for 18 h. MeOH (100 mL) was addedcarefully and the precipitated solid dissolved. The mixture wasconcentrated in vacuo to about 500 mL, cooled to 0 □C, and 10 N NaOH wasadded to adjust the pH to 10-11. This mixture was extracted with EtOAc(3×600 mL) and the combined organic layers were washed with brine, driedover Na₂SO₄, filtered, and concentrated to give the title compound. MS:m/z=207 (M−OH+CH₃CN).

Step E. 1,2-Bis(bromomethyl)-4-nitrobenzene

Phosphorus tribromide (3.90 mL, 41.1 mmol) in Et₂O (50 mL) was addeddrop wise over 1.5 h to a solution of (4-nitro-1,2-phenylene)dimethanolfrom Step D (6.85 g, 37.4 mmol) in Et₂O (150 mL). After 18 h, thereaction mixture was cooled to 0 □C and quenched with H₂O (25 mL). Thelayers were separated and the organic layer was washed with H₂O, thensaturated aqueous NaHCO₃, dried over Na₂SO₄, filtered, and concentratedto give the title compound. MS: m/z=309 (M).

Step F.(±)-5-Nitro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

To a solution of 1,2-bis(bromomethyl)-4-nitrobenzene from Step E (40.9g, 132 mmol) and1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-onefrom Step C (31.5 g, 119 mmol) in DMF (2 L) was added cesium carbonate(129 g, 397 mmol) portion wise, over 5 min. After 18 h, acetic acid (7.6mL) was added and the mixture was concentrated to a volume of about 500mL, then partitioned between EtOAc (1.5 L) and H₂O (1 L). The organiclayer was washed with H₂O (1 L), then brine (500 mL), then dried overNa₂SO₄, filtered, and concentrated. The crude product was purified bysilica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0to 0:100, to give the title compound. MS: m/z=412 (M+1).

Step G.(−)-5-Amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

A mixture of 10% Pd/C (3 g) and5-nitro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-onefrom Step F (19.1 g, 46.4 mmol) was stirred vigorously in EtOH (400 mL)under an atmosphere of hydrogen (ca. 1 atm). After 18 h, the mixture wasfiltered through a pad of Celite, washing extensively with MeOH, and thefiltrate was concentrated to give the crude racemic compound. Theenantiomers were resolved by HPLC, utilizing a Chiralcel OD column andeluting with MeOH. The first major peak to elute was(−)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one,the title compound, and the second major peak to elute was(+)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one.MS: m/z=382 (M+1).

Step H.(−)-5-Amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

A solution of(−)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-onefrom Step G (13.7 g, 35.9 mmol) in MeOH (300 mL) was saturated with HCl(g). The mixture was resaturated with HCl (g) every 30 min until thestarting material was consumed, and then concentrated in vacuo. Theresidue was dissolved in MeOH (150 mL) and treated with ethylene diamine(2.40 mL, 35.9 mmol) and 10 N NaOH (7.20 mL, 72.0 mmol) to adjust themixture to pH 10. After 30 min, the mixture was diluted with H₂O (400mL) and extracted with CHCl₃ (2×1 L). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated in vacuo. The crudematerial was triturated with MeOH (50 mL) to give the title compound.MS: m/z=252 (M+1).

INTERMEDIATE 5

(±)—S-Amino-1,3-dihydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′H)-one

Step A.5,5-Dibromo-4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

Pyridine hydrobromide perbromide (15.6 g, 48.8 mmol) was added in threeportions to a stirred solution of 6-chloro-7-deazapurine (2.50 g, 16.3mmol) at 40° C. in tert-butanol (100 mL). After 3 h, an additionalamount of pyridine hydrobromide perbromide (5.19 g, 16.3 mmol) wasadded. After a further 2 h, the reaction was concentrated in vacuo andpartitioned between EtOAc (200 mL) and H₂O (200 mL). The aqueoussolution was extracted with EtOAc (2×100 mL) and the combined organiclayers were washed with H₂O (50 mL), dried over Na₂SO₄, filtered, andconcentrated in vacuo to give the title compound. MS: m/z=328 (M+1).

Step B. 4-Chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

Zinc (6.05 g, 92.6 mmol) was added to a solution of5,5-dibromo-4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one fromStep A (3.03 g, 9.26 mmol) in THF (20 mL) and saturated aqueous NH₄Cl (5mL). After 3 h, the reaction mixture was concentrated in vacuo andpurified by HPLC using a reversed phase C18 column and eluting with agradient of H₂O:CH₃CN:CF₃CO₂H-90:10:0.1 to 5:95:0.1. Lyophilizationprovided the title compound. MS: m/z=170 (M+1).

Step C.(±)-4′-Chloro-5-nitro-1,3-dihydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′H)-one

Butyllithium (0.29 ml, 0.74 mmol, 2.5 M) was added to a stirred solutionof 4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one from Step B(50.0 mg, 0.295 mmol) at −78° C. in THF (30 mL). After complete additionof butyllithium, N,N,N′,N′-tetramethylethane-1,2-diamine (0.31 mL, 0.77mmol) was added. After 1 h at −78° C.,1,2-bis(bromomethyl)-4-nitrobenzene (91.0 mg, 0.295 mmol, described inIntermediate 4) was added and the reaction warmed to ambienttemperature. After 8 h, the reaction was quenched with H₂O (2 mL) andthe mixture was partitioned between EtOAc (50 mL) and H₂O (50 mL). Theaqueous solution was extracted with EtOAc (3×20 mL). The combinedorganic extracts were washed with brine (100 mL), dried over Na₂SO₄,filtered, and concentrated in vacuo to give the title compound. MS:m/z=317 (M+1).

Step D.(±)-5-Amino-1,3-dihydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′H)-one

To a solution of4′-chloro-5-nitro-1,3-dihydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′H)-onefrom Step C (400 mg, 1.26 mmol) in EtOAc (40 mL) and MeOH (10 mL) wasadded triethylamine (0.880 mL, 6.32 mmol). The mixture was hydrogenatedat 50 psi hydrogen over 10% Pd/C (100 mg). After 24 h and 90 h, anadditional amount of palladium on carbon (100 mg) was added to thereaction mixture and hydrogenation was continued for a total of 180 h.The reaction mixture was filtered through a pad of Celite andconcentrated in vacuo. The residue was purified by HPLC using a reversedphase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H-90:10:0.1 to 5:95:0.1. Lyophilization provided thetitle compound. MS: m/z=253 (M+1).

INTERMEDIATE 6

(±)-5-Amino-4′-chloro-1,3-dihydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′H)-one

To a solution of(=)-4′-chloro-5-nitro-1,3-dihydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′R)-one(40.0 mg, 0.126 mmol, described in Intermediate 5) in EtOAc (10 mL) wasadded triethylamine (0.026 mL, 0.189 mmol). The mixture was hydrogenatedat 30 psi hydrogen over 10% Pd/C (10 mg). After 2 h, the reactionmixture was filtered through a pad of Celite and concentrated in vacuo.The residue was purified by HPLC using a reversed phase C18 column andeluting with a gradient of H₂O:CH₃CN:CF₃CO₂H-90:10:0.1 to 5:95:0.1.Lyophilization provided the title compound. MS: m/z=287 (M+1).

INTERMEDIATE 7

(2-Oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid

Step A. tert-Butyl (2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate

To a stirred mixture of 2-hydroxybenzimidazole (4.00 g, 29.8 mmol) andtert-butyl bromoacetate (5.53 g, 28.3 mmol) in DMF (50 mL) at 0° C. wasadded sodium hydride (1.31 g of a 60% dispersion in mineral oil, 32.8mmol). The mixture was stirred at 0° C. for 1 h, then quenched withsaturated aqueous NaHCO₃ and concentrated in vacuo. The residue waspartitioned between EtOAc (500 mL) and H₂O (300 mL) and the organiclayer was dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The crude product was purified by silica gel chromatography,eluting with a gradient of CH₂Cl₂:EtOAc-100:0 to 0:100, to give thetitle compound. MS: m/z=249 (M+1).

Step B. tert-Butyl(2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate

A mixture of tert-butyl (2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetatefrom Step A (1.75 g, 7.05 mmol), 2-bromopyridine (3.36 mL, 35.2 mmol),copper powder (1.57 g, 24.7 mmol), CuCl (140 mg, 1.41 mmol), and KOAc(2.08 g, 21.1 mmol) in pyridine (30 mL) was heated at 100° C. for 3 h.The cooled mixture was partitioned between EtOAc (150 mL) and 10%aqueous citric acid (100 mL) and the organic layer was dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The crudeproduct was purified by silica gel chromatography, eluting with agradient of hexane:EtOAc-100:0 to 0:100, to give the title compound. MS:m/z=326 (M+1).

Step C. (2-Oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)aceticacid

A solution of tert-butyl(2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate from StepB (2.27 g, 6.98 mmol) in EtOAc (100 mL) at 0° C. was saturated with HCl(g). The mixture was aged at 0° C. for a total of 3 h, and wasre-saturated with HCl every 30 min. The mixture was concentrated invacuo to give the title compound. MS: m/z=270 (M+1).

INTERMEDIATE 8

(2-Oxo-3-pyrimidin-4-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid

Step A.tert-Butyl[3-(6-chloropyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate

To a solution of tert-butyl(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate (130 mg, 0.52 mmol,described in Intermediate 7) in DMF (0.7 mL) was added sodium hydride(15 mg of a 60% dispersion in mineral oil, 0.38 mmol). The mixture wasstirred for 5 min, then 4,6-dichloropyrimidine (234 mg, 1.57 mmol) wasadded and argon was bubbled through the mixture for 5 min. The reactionmixture was heated at 140° C. for 10 min in a microwave reactor. Thecooled mixture was partitioned between CHCl₃ (10 mL) and saturatedaqueous NaHCO₃ (5 mL). The aqueous phase was extracted further withCHCd₃ (10 mL), and the combined organic layers were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The crude product waspurified by silica gel chromatography, eluting with a gradient ofhexane:EtOAc-95:5 to 75:25, to give the title compound. MS: m/z=361(M+1).

Step B. tert-Butyl(2-oxo-3-pyrimidin-4-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate

A mixture oftert-butyl[3-(6-chloropyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetatefrom Step A (260 mg, 0.720 mmol), 10% Pd/C (23 mg) and triethylamine(0.150 mL, 1.08 mmol) in EtOH (5 mL) was stirred under an atmosphere ofhydrogen (ca. 1 atm) for 2 h. The mixture was filtered through a pad ofCelite, washing with EtOH, and the filtrate was concentrated to give thetitle compound. MS: m/z=327 (M+1).

Step C. (2-Oxo-3-pyrimidin-4-yl-2,3-dihydro-1H-benzimidazol-1-yl)aceticacid

Essentially following the procedures described for Intermediate 7, butusing tert-butyl(2-oxo-3-pyrimidin-4-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate fromStep B in place of tert-butyl(2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate, thetitle compound was prepared. MS: m/z=271 (M+1).

INTERMEDIATE 9

[3-(2-Methoxy-2-oxoethyl)-4,6-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]aceticacid

Step A. 4,6-Dimethyl-1,3-dihydro-2H-benzimidazol-2-one

A mixture of 4,6-dimethyl-2-nitroaniline (10.0 g, 60.2 mmol) and 10%Pd/C (1.0 g) in EtOH (300 mL) was stirred under an atmosphere ofhydrogen (ca. 1 atm) for 3 h, then filtered through a Celite pad andconcentrated in vacuo. The crude solid was dissolved in CH₃CN (200 mL)and triphosgene (15.0 g, 50.5 mmol) was added. The mixture was stirredfor 1 h, then H₂O (200 mL) was added slowly and stirring was continuedfor 1 h. The precipitate was isolated by filtration and dried to givethe title compound. MS: m/z=163 (M+1).

Step B. tert-Butyl(4,6-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate

To a stirred solution of 4,6-dimethyl-1,3-dihydro-2H-benzimidazol-2-onefrom Step A (7.15 g, 44.1 mmol) in DMF (200 mL) was added sodium hydride(1.76 g of a 60% dispersion in mineral oil, 44.1 mmol) over 2 min. Themixture was stirred for 20 min, then tert-butyl bromoacetate (8.17 g,41.9 mmol) in DMF (40 mL) was added and stirring was continued for 1 h.The reaction mixture was diluted with H₂O (400 mL) carefully and a solidprecipitated. The mixture was aged for 5 min, then filtered to give acrude solid, which was purified by silica gel chromatography, elutingwith a gradient of CH₂Cl₂:EtOAc-100:0 to 40:60, to provide the titlecompound. MS: m/z=277 (M+1).

Step C.tert-Butyl[3-(2-methoxy-2-oxoethyl)-4,6-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate

To a solution of tert-butyl(4,6-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate from Step B(100 mg, 0.36 mmol) in DMF (3 mL) was added sodium hydride (17 mg of a60% dispersion in mineral oil, 0.43 mmol) followed by methylbromoacetate (0.041 mL, 0.43 mmol) and the reaction mixture was stirredfor 2 h. The reaction was purified directly by HPLC using a reversedphase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H-90:10:0.1 to 5:95:0.1. Lyophilization of theproduct-containing fractions afforded the title compound. MS: m/z=349(M+1).

Step D.[3-(2-Methoxy-2-oxoethyl)-4,6-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]aceticacid

Essentially following the procedures described for Intermediate 7, butusing tert-butyl[3-(2-methoxy-2-oxoethyl)-4,6-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetatefrom Step C in place of tert-butyl(2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate, thetitle compound was prepared. MS: m/z=293 (M+1).

INTERMEDIATE 10

{3-[2-(Dimethylamino)-2-oxoethyl]-5,7-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}aceticacid

Step A. Methyl{3-[2-(dimethylamino)-2-oxoethyl]-5,7-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetate

A solution of[3-(2-methoxy-2-oxoethyl)-4,6-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]aceticacid (Intermediate 9) (305 mg, 1.04 mmol), N,N-dimethylaminehydrochloride (128 mg, 1.60 mmol), EDC (300 mg, 1.60 mmol), HOBT (240mg, 1.60 mmol), and N, N-diisopropylethylamine (0.909 mL, 5.20 mmol)were stirred for 16 h at ambient temperature in DMF (3 mL). The mixturewas partitioned between CH₂Cl₂ (10 mL) and saturated NaHCO₃ (10 mL) andthe organic layer was dried over Na₂SO₄, filtered, and concentrated togive the compound. MS: m/z=320 (M+1).

Step B.{3-[2-(Dimethylamino)-2-oxoethyl]-5,7-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}aceticacid

Lithium hydroxide (131 mg, 3.12 mmol) was added to a solution of methyl{3-[2-(dimethylamino)-2-oxoethyl]-5,7-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetatefrom Step A (333 mg, 1.04 mmol) in THF (3 mL) and H₂O (1 mL). After 72h, H₂O was added and the precipitate was collected by filtration to givethe title compound. MS: nil/z=306 (M+1).

INTERMEDIATE 11

2-Oxo-1′-(2,2,2-trifluoroethyl)-spiro[indoline-3,4°-piperidine]-1-aceticacid

Step A. 1′-(2,2,2-trifluoroethyl)-spiro[indoline-3,4′-piperidin]-2-one

A mixture of spiro[indoline-3,4′-piperidin]-2-one, [PCT Int. Appl. WO0145707 A1 (2001)] trifluoroacetic acid salt (3.66 g, 11.6 mmol),2,2,2-trifluoroethyl trifluoromethanesulfonate (1.63 mL, 11.6 mmol), andtriethylamine (8.06 mL, 57.9 mmol) in acetone (30 mL) was heated atreflux for 16 h. The mixture was allowed to cool, and the solventremoved under reduced pressure. The residue was taken up in CH₂Cl₂ (50mL) and washed with saturated aqueous NaHCO₃ (50 mL). The aqueous layerwas further extracted with CH₂Cl₂ (2×25 mL). The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated in vacuo to give thetitle compound. MS: m/z=285 (M+1).

Step B. tert-Butyl2-oxo-1′-(2,2,2-trifluoroethyl)-spiro[indoline-3,4′-piperidine]-1-acetate

To a stirred solution of1′-(2,2,2-trifluoroethyl)-spiro[indoline-3,4′-piperidin]-2-one from StepA (3.30 g, 11.6 mmol) in DMF (10 mL) was added sodium hydride (697 mg ofa 60% dispersion in mineral oil, 17.4 mmol) at 0° C. The mixture wasstirred at 0° C. for 45 min, then tert-butyl bromoacetate (1.88 mL, 12.8mmol) was added and stirring was continued at room temperature for 72 h.The reaction mixture was quenched with H₂O. The aqueous layer wasextracted with CH₂Cl₂ (3×50 mL). The combined CH₂Cl₂ layers were driedover Na₂SO₄, filtered, and concentrated in vacuo. The crude product waspurified by silica gel chromatography, eluting with a gradient ofhexane:EtOAc-100:0 to 80:20, to provide the title compound. MS: m/z=399(M+1).

Step C.2-Oxo-1′-(2,2,2-trifluoroethyl)-spiro[indoline-3,4′-piperidine]-1-aceticacid

A solution of the tert-butyl2-oxo-1′-(2,2,2-trifluoroethyl)-spiro[indoline-3,4′-piperidine]-1-acetatefrom Step B (3.19 g, 8.01 mmol) in CH₂Cl₂ (16 mL) and CF₃CO₂H (5 mL) wasstirred at ambient temperature for 17 h. Added CF₃CO₂H (1 mL) andstirred 1 additional hour. The mixture was concentrated in vacuo. To theresulting solid was added an HCl solution (10 mL, 2.0 M in Et₂O) and thesolution concentrated in vacuo. Repeated two more times to produce thehydrochloride salt of the title compound as a white solid. MS: m/z=343(M+1).

INTERMEDIATE 12

[1′-(2,2,2-Trifluoroethyl)spiro[indole-3,4′-piperidin]-1 (21)-yl]aceticacid

Step A.1′-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,4′-piperidine]

A mixture of 1-acetyl-1,2-dihydrospiro[indole-3,4′-piperidine]hydrochloride, [Chen et al. Tetrahedron Lett. 1996, 37(30), 5233-5234](200 mg, 0.750 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate(0.128 mL, 0.900 mmol), and triethylamine (0.522 mL, 3.75 mmol) inacetone (2 mL) was heated at reflux for 15 h. The mixture was allowed tocool, and the solvent removed under reduced pressure. The residue wastaken up in CH₂Cl₂ (10 mL) and washed with saturated aqueous NaHCO₃ (10mL). The aqueous layer was further extracted with CH₂Cl₂ (2×10 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by silica gelchromatography, eluting with a gradient of hexane:EtOAc-100:0 to 50:50,to provide the title compound. MS: m/z=271 (M+1).

Step B.tert-Butyl[1′-(2,2,2-trifluoroethyl)spiro[indole-3,4′-piperidin]-1(2H)-yl]acetate

A solution of1′-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,4′-piperidine] fromStep A (64.0 mg, 0.237 mmol), potassium carbonate (49.0 mg, 0.355 mmol),potassium iodide (59.0 mg, 0.355 mmol), and tert-butyl bromoacetate(0.042 mL, 0.284 mmol) in DMF (2 mL) was stirred at 50° C. for 1 h. Thereaction mixture was quenched with H₂O. The aqueous layer was extractedwith CH₂Cl₂ (3×20 mL), and the combined organic layers were dried overNa₂SO₄, filtered, and concentrated in vacuo to provide the titlecompound. MS: m/z=385 (M+1).

Step C.[1′-(2,2,2-Trifluoroethyl)spiro[indole-3,4′-piperidin]-1(2-H)-yl]aceticacid

A solution oftert-butyl[1′-(2,2,2-trifluoroethyl)spiro[indole-3,4′-piperidin]-1(2H)-yl]acetate(91.0 mg, 0.237 mmol) from Step B in CH₂Cl₂ (2 mL) and CF₃CO₂H (1 mL)was stirred at ambient temperature for 6 h. Added CF₃CO₂H (1 mL) andstirred 1 additional hour. The mixture was concentrated in vacuo. Thecrude product was partitioned between CH₂Cl₂ (20 mL) and saturatedNaHCO₃ (20 mL). The layers were separated and the aqueous layer wasfurther extracted with CH₂Cl₂ (2×20 mL). The combined CH₂Cl₂ layers weredried over Na₂SO₄, filtered, and concentrated in vacuo to provide thetitle compound. MS: m/z=329 (M+1).

INTERMEDIATE 13

(±)-{3-[4-(Methylsulfinyl)-1,3-thiazol-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}aceticacid

Step A. 1-(4-Bromo-1,3-thiazol-2-yl)-1,3-dihydro-2H-benzimidazol-2-one

A mixture of 2-hydroxybenzimidazole (1.20 g, 8.95 mmol),2,4-dibromothiazole (6.50 g, 26.8 mmol), copper powder (1.42 g, 22.4mmol), CuCl (177 mg, 1.79 mmol), and KOAc (2.20 g, 22.4 mmol) inpyridine (10 mL) were heated at 60° C. for 2 h. The cooled mixture waspartitioned between EtOAc (40 mL) and 10% aqueous citric acid (20 mL)and the organic layer was dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The crude product was purified by silica gelchromatography, eluting with a gradient of hexane:EtOAc-100:0 to 50:50,to give the title compound. MS: m/z=298 (M+1).

Step B.1-[4-(Methylthio)-1,3-thiazol-2-yl]-1,3-dihydro-2H-benzimidazol-2-one

A mixture of1-(4-bromo-1,3-thiazol-2-yl)-1,3-dihydro-2H-benzimidazol-2-one from StepA (1.00 g, 3.38 mmol), sodium methanethiolate (710 mg, 10.13 mmol), andcopper iodide (643 mg, 3.38 mmol) in DMF (6 mL) were heated at 140° C.An additional amount of sodium methanethiolate (474 mg, 6.76 mmol) wasadded to the mixture after 3 h and 16 h and the reaction continuedstirring at 140° C. After 20 h, the cooled mixture was partitionedbetween saturated aqueous NaHCO₃ (30 mL) and CHCl₃ (50 mL). The aqueousphase was extracted further with CHCl₃ (50 mL) and the combined organiclayers were dried (Na₂SO₄), filtered, and concentrated under reducedpressure to give the title compound. MS: m/z=264 (M+1).

Step C. tert-Butyl{3-[4-(methylthio)-1,3-thiazol-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetate

To a stirred mixture of1-[4-(methylthio)-1,3-thiazol-2-yl]-1,3-dihydro-2H-benzimidazol-2-onefrom Step B (710 mg, 2.67 mmol) and tert-butyl bromoacetate (578 mg,2.97 mmol) in DMF (15 mL) at 0° C. was added sodium hydride (194 mg of a60% dispersion in mineral oil, 4.85 mmol). The mixture was stirred at 0°C. for 15 min, then quenched with saturated aqueous NaHCO₃ and extractedwith CH₂Cl₂ (2×35 mL). The combined organic layers were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The crudeproduct was purified by silica gel chromatography, eluting with agradient of hexane:EtOAc-100:0 to 70:30, to give the title compound. MS:m/z=378 (M+1).

Step D.(±)-tert-Butyl{3-[4-(methylsulfinyl)-1,3-thiazol-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetate

A solution of OXONE® in H₂O (0.5 mL) was added to a solution oftert-butyl{3-[4-(methylthio)-1,3-thiazol-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetatefrom Step C (110 mg, 0.291 mmol) in isopropanol (1 mL) and CHCl₃ (1 mL)at 0° C. After 2 h, the mixture was quenched with saturated aqueous NaCland extracted with CHCl₃ (2×10 mL). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated under reduced pressure.The crude product was purified by silica gel chromatography, elutingwith a gradient of hexane:EtOAc-90:10 to 50:50, to give the titlecompound. MS: m/z=394 (M+1).

Step E.(±)-{3-[4-(Methylsulfinyl)-1,3-thiazol-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}aceticacid

(±)-tert-Butyl{3-[4-(methylsulfinyl)-1,3-thiazol-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetatefrom Step D (100 mg, 0.254 mmol) was dissolved in CF₃CO₂H (3 mL) andCH₂Cl₂ (3 mL) and the mixture was stirred at ambient temperature for 3h, then concentrated in vacuo to give the title compound. MS: m/z=338(M+1).

INTERMEDIATE 14

{3-[4-(Methoxycarbonyl)-1,3-thiazol-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}aceticacid

Step A.tert-Butyl[3-(4-bromo-1,3-thiazol-2-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate

Essentially following the procedures described for Intermediate 7, butusing 2,4-dibromothiazole in place of 2-bromopyridine, the titlecompound was prepared. MS: m/z=412 (M+1).

Step B. Methyl2-[3-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]-1,3-thiazole-4-carboxylate

To a suspension oftert-butyl[3-(4-bromo-1,3-thiazol-2-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetatefrom Step A (250 mg, 0.609 mmol) and triethylamine (0.850 mL, 6.09 mmol)in MeOH (5 mL) was added bis(triphenylphosphine)palladium (II) chloride(86.0 mg, 0.122 mmol). The reaction mixture was heated at reflux underan atmosphere of carbon monoxide (ca 1 atm) for 48 h, then partitionedbetween CHCl₃ (20 mL) and saturated aqueous NaHCO₃ (5 mL). The organiclayer was dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The crude product was purified by silica gel chromatography,eluting with a gradient of hexane:EtOAc-100:0 to 60:40, to give thetitle compound. MS: m/z=412 (M+23).

Step C.{3-[4-(Methoxycarbonyl)-1,3-thiazol-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}aceticacid

A solution of methyl2-[3-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]-1,3-thiazole-4-carboxylatefrom Step B (195 mg, 0.501 mmol) in EtOAc (3 mL) at 0° C. was saturatedwith HCl (g) for 5 min. After 15 min, the reaction was re-saturated withHCl for another 5 min. The mixture was concentrated in vacuo to give thetitle compound as a white solid. MS: m/z=334 (M+1).

INTERMEDIATE 15

{3-[4-(Ethoxycarbonyl)phenyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}aceticacid

Step A. Ethyl 4-[(2-nitrophenyl)amino]benzoate

A mixture of ethyl 4-aminobenzoate (1.00 g, 6.05 mmol) and2-fluoronitrobenzene (0.64 mL, 6.05 mmol) was heated at 160° C. for 18h. The crude product was purified by silica gel chromatography, elutingwith hexane:EtOAc-70:30, to give the title compound. MS: m/z=287 (M+1).

Step B. Ethyl 4-[(2-aminophenyl)amino]benzoate

A mixture of ethyl 4-[(2-nitrophenyl)amino]benzoate from Step A (755 mg,2.64 mmol) and 10% Pd/C (505 mg) in EtOH (25 mL) was stirred under anatmosphere of hydrogen (ca. 1 atm) for 4 h. The mixture was filteredthrough a pad of Celite, washing with EtOH, and the filtrate wasconcentrated to give the title compound. MS: m/z=257 (M+1).

Step C. Ethyl 4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)benzoate

A mixture of ethyl 4-[(2-aminophenyl)amino]benzoate from Step B (442 mg,1.72 mmol) and 1,1′-carbonyldiimidazole (652 mg, 4.02 mmol) in THF (10mL) was heated at 75° C. for 3 h. The cooled mixture was partitionedbetween EtOAc (100 mL) and 10% aqueous citric acid (50 mL). The organiclayer was washed with H₂O (30 mL), then brine (30 mL), then dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The crudeproduct was purified by silica gel chromatography, eluting with agradient of hexane:EtOAc-95:5 to 75:25, to give the title compound. MS:m/z=283 (M+1).

Step D. Ethyl4-[3-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]benzoate

To a stirred solution of ethyl4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)benzoate from Step C (590 mg,2.09 mmol) in DMF (10 mL) at 0° C. was added sodium hydride (104 mg of a60% dispersion in mineral oil, 2.60 mmol). The mixture was stirred for 5min, then tert-butyl bromoacetate (489 mg, 2.51 mmol) was added andstirring was continued for 3 h. The reaction mixture was partitionedbetween EtOAc (200 mL) and H₂O (100 mL). The organic layer was washedwith H₂O (50 mL), then brine (50 mL), then dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The crude product was purifiedby silica gel chromatography, eluting with a gradient ofhexane:EtOAc-100:0 to 0:100, to give the title compound. MS: m/z=397(M+1).

Step E.{3-[4-(Ethoxycarbonyl)phenyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}aceticacid

Essentially following the procedures described for Intermediate 7, butusing ethyl4-[3-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]benzoatefrom Step D in place of tert-butyl(2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate, thetitle compound was prepared. MS: m/z=341 (M+1).

INTERMEDIATE 16

(±)-(2-Oxo-3-tetrahydrofuran-3-yl-2,3-dihydro-1H-benzimidazol-1-yl)aceticacid

Step A. (±)-N-(2-Nitrophenyl)tetrahydrofuran-3-amine

A solution of N,N-diisopropylethylamine (3.20 mL, 18.4 mmol),1-fluoro-2-nitrobenzene (0.484 mL, 4.59 mmol), and(±)-tetrahydrofuran-3-amine (400 mg, 4.59 mmol) in n-butanol (10 mL) washeated to 180° C. in a microwave reactor. After 20 min, the reaction wasallowed to cool to ambient temperature and concentrated. Purification bysilica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0to 0:100, gave the title compound. MS: m/z=209 (M+1).

Step B.(±)-(2-Oxo-3-tetrahydrofuran-3-yl-2,3-dihydro-1H-benzimidazol-1-yl)aceticacid

Essentially following the procedures described for Intermediate 15, butusing (±)-N-(2-nitrophenyl)tetrahydrofuran-3-amine in place of ethyl4-[(2-nitrophenyl)amino]benzoate, the title compound was prepared. MS:m/z=263 (M+1).

INTERMEDIATE 17

(2-Oxo-3-tetrahydro-2H-thiopyran-4-yl-2,3-dihydro-1H-benzimidazol-1-yl)aceticacid

Step A. tert-Butyl2-oxo-3-tetrahydro-2H-thiopyran-4-yl-2,3-dihydro-1H-benzimidazole-1-carboxylate

Diethyl azodicarboxylate (446 mg, 2.56 mmol) was added to a solution oftert-butyl 2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (J. Org.Chem., 1995, 60, 1565-1582) (500 mg, 2.13 mmol), triphenylphosphine (672mg, 2.56 mmol), and tetrahydro-2H-thiopyran-4-ol (Chem. Comm., 2002, 10,1070-1071) (303 mg, 2.56 mmol) in THF (10 mL). After 20 h, the reactionwas concentrated in vacuo and the crude product purified by silica gelcolumn chromatography, eluting with a gradient of hexane:EtOAc-100:0 to95:5, to give the title compound. MS: m/z=335 (M+1).

Step B. 1-Tetrahydro-2H-thiopyran-4-yl-1,3-dihydro-2H-benzimidazol-2-one

CF₃CO₂H (1 mL) was added to a solution of tert-butyl2-oxo-3-tetrahydro-2H-thiopyran-4-yl-2,3-dihydro-1H-benzimidazole-1-carboxylatefrom Step A (210 mg, 0.628 mmol) in CH₂Cl₂ (3 mL). After 2 h, themixture was concentrated in vacuo to give the title compound. MS:m/z=235 (M+1).

Step C. tert-Butyl(2-oxo-3-tetrahydro-2H-thiopyran-4-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate

Sodium hydride (68.3 mg of a 60% dispersion in mineral oil, 1.71 mmol)followed by tert-butyl bromoacetate (0.189 mL, 1.28 mmol) was added to asolution of1-tetrahydro-2H-thiopyran-4-yl-1,3-dihydro-2H-benzimidazol-2-one fromStep B (200 mg, 0.854 mmol) in DMF (5 mL). After 1 h, the reaction wasquenched with H₂O (10 mL) and extracted with CH₂Cl₂ (10 mL). The organiclayer was washed with saturated NaHCO₃ (5 mL), dried over MgSO₄,filtered, and concentrated in vacuo. Purification by silica gelchromatography, eluting with a gradient of hexane:EtOAc-100:0 to 50:50,gave the title compound. MS: m/z=349 (M+1).

Step D.(2-Oxo-3-tetrahydro-2H-thiopyran-4-yl-2,3-dihydro-1H-benzimidazol-1-yl)aceticacid

CF₃CO₂H (1 mL) was added to a solution of tert-butyl(2-oxo-3-tetrahydro-2H-thiopyran-4-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetatefrom Step C (169 mg, 0.485 mmol) in CH₂Cl₂ (3 mL). After 3 h, themixture was concentrated in vacuo to give the title compound. MS:m/z=293 (M+1).

INTERMEDIATE 18

(2-Oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-1(2H)-yl)aceticacid

Step A. 2′,3′,5′,6′-Tetrahydrospiro[indole-3,4′-pyran]-2(1H)-one

Butyllithium (2.5 M in hexanes, 3.76 mL, 9.39 mmol) was added to asolution of oxindole (500 mg, 3.76 mmol) at −78° C. in THF (40 mL).After complete addition, N,N,N′,N′-tetramethylethane-1,2-diamine (1.48mL, 9.76 mmol) was added, maintaining the internal temperature <−70° C.After 1 h at −78° C., 2-iodoethyl ether (4.90 g, 15.0 mmol) was addedand the reaction warmed to ambient temperature. After 48 h the reactionwas quenched with H₂O (5 mL) and the mixture was partitioned betweenEtOAc (100 mL) and H₂O (100 mL). The aqueous solution was extracted withEtOAc (3×50 mL) and the combined organic layers were washed with brine(20 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo.Purification by silica gel chromatography, eluting with a gradient ofCH₂Cl₂:MeOH-100:0 to 97:3, gave the title compound. MS: m/z=204 (M+1).

Step B. tert-Butyl(2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-1(2H)-yl)acetate

Sodium hydride (8.00 mg of a 60% dispersion in mineral oil, 0.207 mmol)was added to a solution of2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-2(1H)-one from Step A(35.0 mg, 0.172 mmol) in DMF (1 mL) at 0° C. After 1 hr, tert-butylbromoacetate (0.280 mL, 0.189 mmol) was added and the reaction warmed toambient temperature. After 18 h, the reaction was partitioned betweenCH₂Cl₂ (10 mL) and saturated NH₄Cl (10 mL). The organic layer was driedover Na₂SO₄, filtered, and concentrated in vacuo to give the titlecompound. MS: m/z=318 (M+1).

Step C.(2-Oxo-2′,3′,5′,6-tetrahydrospiro[indole-3,4′-pyran]-1(2H)-yl)aceticacid

CF₃CO₂H (1 mL) was added to a solution of tert-butyl(2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-1(2H)-yl)acetatefrom Step B (55.0 mg, 0.173 mmol) in CH₂Cl₂ (3 mL). After 3 h, themixture was concentrated in vacuo to give the title compound. MS:m/z=262 (M+1).

INTERMEDIATE 19

(2′,4-Dioxospiro[cyclohexane-1,3′-indol]-1′(2′H)-yl)acetic acid

Step A. 4H-Spiro[cyclohexane-13′-indole]-2′,4(1′H)-dione

Methyl acrylate (10.5 mL, 116.4 mmol) was added over 1 h to a solutionof oxindole (5.00 g, 37.6 mmol) and potassium tert-butoxide (211 mg,1.88 mmol) in dimethyl sulfoxide (19 mL) at 45° C. After 1 h, potassiumtert-butoxide (9.48 g, 84.5 mmol) was added in portions over 30 minwhile maintaining the internal temperature at 55-60° C. The mixture wasconcentrated in vacuo, poured into H₂O (100 mL), and heated to 80° C.After 23 h, the reaction was extracted with EtOAc (3×100 mL) and thecombined organics were dried over Na₂SO₄, filtered, and concentrated togive the desired product. MS: m/z=216 (M+1).

Step B. tert-Butyl(2′,4-dioxospiro[cyclohexane-1,3′-indol]-1′(2′H)-yl)acetate

Cesium carbonate (1.19 g, 3.64 mmol) was added to a solution of4H-spiro[cyclohexane-1,3′-indole]-2′,4(1′H)-dione from Step A (523 mg,2.43 mmol) and tert-butyl bromoacetate (0.431 mL, 2.92 mmol) in DMF (10mL). After 22 h, the mixture was partitioned between H₂O (100 mL) andCH₂Cl₂ and extracted with CH₂Cl₂ (3×75 mL). The combined organics werewashed with H₂O, dried over Na₂SO₄, filtered, and concentrated in vacuoto give the desired product. MS: m/z=330 (M+1).

Step C. (2′,4-Dioxospiro[cyclohexane-1,3′-indol]-1′(2′H)-yl)acetic acid

HCl (g) was bubbled into a solution of tert-butyl(2′,4-dioxospiro[cyclohexane-1,3′-indol]-1′(2′H)-yl)acetate from Step B(800 mg, 2.43 mmol) in EtOAc (10 mL) for 5 min. After 3 h, the reactionwas concentrated in vacuo to give the desired product. MS: m/z=274(M+1).

INTERMEDIATE 20

Sodium(5-bromo-2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)acetate

Step A.3,3-Bis[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,3-dihydro-2H-indol-2-one

Potassium tert-butoxide (10.1 g, 90.1 mmol) was added to a solution ofoxindole (3.00 g, 22.5 mmol) in THF (50 mL) at −75° C. and the mixturewas allowed to warm to ambient temperature. After 1 h, the reaction wascooled to −75° C. and 2-(2-bromoethoxy)tetrahydro-2H-pyran (7.15 mL,47.3 mmol) was added dropwise over 10 min. After 18 h, the mixture waspartitioned between EtOAc (100 mL) and H₂O (100 mL). The layers wereseparated and the aqueous layer was further extracted with EtOAc (2×50mL). The combined organics were dried over Na₂SO₄, filtered, andconcentrated in vacuo. Purification by silica gel chromatography,eluting with a gradient of hexane:EtOAc-100:0 to 80:20, gave the titlecompound. MS: 71/z=390 (M+1).

Step B. 5-Bromo-3,3-bis(2-bromoethyl)-1,3-dihydro-2H-indol-2-one

Bromine (0.712 mL, 13.9 mmol) was added to a solution of3,3-bis[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,3-dihydro-2H-indol-2-onefrom Step A (1.23 g, 3.16 mmol) and triphenylphosphine (3.64 g, 13.9mmol) in CH₂Cl₂ (20 mL) at 0° C. After 22 h, the mixture was partitionedbetween CH₂Cl₂ (50 mL) and H₂O (50 mL). The layers were separated andthe aqueous layer was further extracted with CH₂Cl₂ (2×25 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. Purification by silica gel chromatography,eluting with a gradient of CH₂Cl₂:MeOH-100:0 to 90:10, gave the titlecompound. MS: m/z=427 (M+1).

Step C.5-Bromo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-2(1H)-one

Sodium sulfide (292 mg, 3.75 mmol) was added to a solution of5-bromo-3,3-bis(2-bromoethyl)-1,3-dihydro-2H-indol-2-one from Step B(532 mg, 1.25 mmol) in DMF (2 mL) and the solution heated to 50° C.After 2.5 h, the mixture was partitioned between CH₂Cl₂ (20 mL) and H₂O(20 μL). The layers were separated and the aqueous layer was furtherextracted with CH₂Cl₂ (2×10 mL). The combined organic layers were driedover Na₂SO₄, filtered, and concentrated in vacuo to give the titlecompound. MS: m/z=300 (M+1).

Step D. Ethyl(5-bromo-2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)acetate

Cesium carbonate (610 mg, 1.87 mmol) was added to a solution of5-bromo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-2(1H)-onefrom Step C (372 mg, 1.25 mmol) and ethyl bromoacetate (0.166 mL, 1.50mmol) in DMF (2 mL). After 16 h, H₂O (5 mL) was added to the reactionand the resulting precipitate was collected by filtration to give thetitle compound. MS: m/z=386 (M+1).

Step E. Sodium(5-bromo-2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)acetate

5 M Sodium hydroxide solution (0.748 mL, 3.74 mmol) was added to asolution of ethyl(5-bromo-2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)acetatefrom Step D (479 mg, 1.25 mmol) in EtOH(2 mL) and the mixture was heatedto 60° C. After 14 h, H₂O (5 mL) was added to the reaction and theresulting precipitate was collected by filtration to give the desiredproduct. MS: m/z=357 (M+1).

INTERMEDIATE 21

(2-Oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)aceticacid

Step A.(2-Oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)aceticacid

Ethylmagnesium bromide (3 M in Et₂O, 0.272 mL, 0.817 mmol) was added toa solution of sodium(5-bromo-2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)acetate(194 mg, 0.545 mmol, described in Intermediate 20) in THF (5 mL) at −78°C., followed by the addition of tert-butyllithium (1.7 M in pentane,0.801 mL, 1.36 mmol). After 1 h, the reaction was quenched with H₂O andpartitioned between EtOAc (20 mL) and 10% HCl (20 mL). The layers wereseparated and the aqueous layer was further extracted with EtOAc (2×10mL). The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo to give the title compound. MS: m/z=278 (M+1).

INTERMEDIATE 22

[3-(2-Methoxy-2-oxoethyl)-4,6-dimethyl-1H-indol-1-yl]acetic acid

Step A. [(4,6-Dimethyl-1H-indol-3-yl)methyl]dimethylamine

A mixture of 4,6-dimethyl-1H-indole (Cho et al., Tetrahedron, 2001, 57,3321-3330) (93.0 mg, 0.640 mmol) and N,N,N,N′-tetramethylmethanediamine(98.0 mg, 0.961 mmol) in AcOH (3 mL) was stirred at ambient temperaturefor 2 h. The reaction mixture was partitioned between EtOAc (20 mL) andsaturated NaHCO₃ (10 mL). The layers were separated and the organiclayer was dried over Na₂SO₄, filtered, and concentrated in vacuo to givethe title compound.

Step B. (4,6-Dimethyl-1H-indol-3-yl)acetonitrile

A solution of [(4,6-dimethyl-1H-indol-3-yl)methyl]dimethylamine fromStep A (98.0 mg, 0.484 mmol) and potassium cyanide (315 mg, 4.84 mmol)in DMF (2 mL) and H₂O (2 mL) was heated at 100° C. for 2 h. The reactionmixture was partitioned between EtOAc (20 mL) and saturated NaCl (10mL). The layers were separated and the organic layer was dried overNa₂SO₄, filtered, and concentrated in vacuo. Purification of the crudeproduct by silica gel chromatography, eluting with a gradient ofCH₂Cl₂:MeOH-100:0 to 98:2, gave the title compound. MS: m/z=185 (M+1).

Step C. Methyl (4,6-dimethyl-1H-indol-3-yl)acetate

HCl (g) was bubbled through a solution of(4,6-dimethyl-1H-indol-3-yl)acetonitrile from Step B (83.0 mg, 0.450mmol) in MeOH (5 mL). The reaction mixture was stirred for 30 min, thenH₂O (1 mL) was added and stirring was continued for 2 h. The MeOH wasremoved under vacuum and the reaction mixture was extracted with EtOAc(5 mL). The organic layer was dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was dissolved in MeOH (2 mL)containing a drop of conc. H₂SO₄ and the resulting mixture was stirredfor 16 h. The reaction mixture was partitioned between EtOAc (10 mL) andsaturated NaCl (5 mL). The layers were separated and the organic layerwas dried over Na₂SO₄, filtered, and concentrated in vacuo. Purificationof the crude product by silica gel chromatography, eluting with agradient of hexane:EtOAc-100:0 to 80:20, gave the title compound. MS:m/z=218 (M+1).

Step D. [3-(2-Methoxy-2-oxoethyl)-4,6-dimethyl-1H-indol-1-yl]acetic acid

Essentially following the procedures described for Intermediate 19, butusing methyl (4,6-dimethyl-1H-indol-3-yl)acetate from Step C in place of4H-spiro[cyclohexane-1,3′-indole]-2′,4(1′H)-dione the title compound wasprepared. MS: m/z=276 (M+1).

INTERMEDIATE 23

[3-(2-Methoxy-2-oxoethyl)-1H-pyrrolo[2,3-c]pyridin-1-yl]acetic acid

Step A.[(4-Bromo-7-chloro-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl]dimethylamine

A mixture of 4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridine (Zhang et al.,J. Org. Chem., 2002, 67, 2345-2347) (200 mg, 0.864 mmol), formaldehyde(37 wt. % in H₂O, 0.500 mL, 6.17 mmol), and dimethylamine (40 wt. % inH₂O, 1.00 mL, 8.88 mmol) in AcOH (6 mL) was heated in a microwavereactor at 100° C. for 40 min. The solvent was removed under reducedpressure. The crude product was partitioned between CH₂Cl₂ (15 mL) andsaturated NaHCO₃ (10 mL). The layers were separated and the organiclayer was dried over Na₂SO₄, filtered, and concentrated in vacuo.Purification of the crude product by silica gel chromatography, elutingwith a gradient of CH₂Cl₂:MeOH-100:0 to 90:10, gave the title compound.MS: m/z=290 (M+1).

Step B. (4-Bromo-7-chloro-1H-pyrrolo[2,3-c]pyridin-3-yl)acetonitrile

A solution of[(4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl]dimethylaminefrom Step A (195 mg, 0.676 mmol) and potassium cyanide (440 mg, 6.76mmol) in DMF (0.5 mL) and H₂O (0.5 mL) was heated at 100° C. for 2 h.The reaction mixture was partitioned between EtOAc (20 mL) and H₂O (10mL). The layers were separated and the organic layer was dried overNa₂SO₄, filtered, and concentrated in vacuo to give the title compound.MS: m/z=272 (M+1).

Step C. Methyl (4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridin-3-yl)acetate

HCl (g) was bubbled through a solution of(4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridin-3-yl)acetonitrile from Step B(165 mg, 0.610 mmol) in MeOH (5 mL) and the reaction mixture was stirredfor 2 h. The MeOH was removed under reduced pressure and H₂O (1 mL) andsaturated NaHCO₃ (5 mL) were added. The reaction mixture was extractedwith EtOAc (10 mL). The organic layer was washed with saturated NaHCO₃(5 mL) and saturated NaCl (5 mL), dried over Na₂SO₄, filtered, andconcentrated in vacuo. Purification of the crude product by silica gelchromatography, eluting with a gradient of CH₂Cl₂:MeOH-100:0 to 90:10,gave the title compound. MS: m/z=305 (M+1).

Step D. tert-Butyl methyl2,2′-(4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridine-1,3-diyl)diacetate

Cesium carbonate (185 mg, 0.568 mmol) was added to a solution of methyl(4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridin-3-yl)acetate from Step C (115mg, 0.379 mmol) and tert-butyl bromoacetate (0.0810 mL, 0.417 mmol) inDMF (2 mL). After 30 min, the mixture was partitioned between H₂O (5 mL)and EtOAc (10 mL). The layers were separated and the organic layer wasdried over Na₂SO₄, filtered, and concentrated in vacuo to give the titlecompound. MS: m/z=419 (M+1).

Step E.[4-Bromo-7-chloro-3-(2-methoxy-2-oxoethyl)-1H-pyrrolo[2,3-c]pyridin-1-yl]aceticacid

1 M Sodium hydroxide solution (0.300 mL, 3.00 mmol) was added to asolution of tert-butyl methyl2,2′-(4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridine-1,3-diyl)diacetate fromStep D (153 mg, 0.366 mmol) in MeOH (3 mL) and the mixture was stirredfor 2 h at ambient temperature. The reaction was quenched by theaddition of 1 M HCl (0.300 mL) and the solvent removed under reducedpressure. The crude product was purified by HPLC using a reversed phaseC18 column and eluting with a gradient of H₂O:CH₃CN:CF₃CO₂H-90:10:0.1 to5:95:0.1 to provide the title compound. MS: m/z=363 (M+1).

Step F. [3-(2-Methoxy-2-oxoethyl)-1H-pyrrolo[2,3-c]pyridin-1-yl]aceticacid

A mixture of[4-bromo-7-chloro-3-(2-methoxy-2-oxoethyl)-1H-pyrrolo[2,3-c]pyridin-1-yl]aceticacid from Step E (27.0 mg, 0.075 mmol) and 10% Pd/C (10 mg) in MeOH (5mL) was stirred under an atmosphere of hydrogen (ca. 1 atm) for 2 h. Themixture was filtered through a pad of Celite, washing with MeOH, and thefiltrate was concentrated in vacuo to give the title compound. MS:m/z=249 (M+1).

INTERMEDIATES 24-36

Essentially following analogous procedures to those outlined forIntermediates 7-23, the compounds listed in Table 1 were prepared. Themost relevant analogous procedure for each intermediate is listed in theTable. The requisite starting materials were commercially available,described in the literature, or readily synthesized by one skilled inthe art of organic synthesis. In some cases, straightforward protectinggroup strategies were applied.

TABLE 1

MS Relevant Literature Intermediate R^(c) (M + 1) Intermediate Reference24

285 7 25

271 7 26

271 7 27

271 8 28

322 13 29

354 13 30

362 16 31

328 7 32

361 11 33

276 7 34

324 22 Snieckus et al., Org. Lett., 2002, 4(5), 815-818. 35

325 22 Snieckus et al., Org Lett., 2002, 4(5), 815-818. 36

271 8 37

264 10 38

304 22

EXAMPLE 1

(±)-N-(2′,5′-Dioxo-1,3-dihydrospiro[indene-2,3′-pyrrolidin]-5-yl)-2-(2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetamide

A solution of(±)-5-amino-1,3-dihydro-2′H,5′H-spiro[indene-2,3′-pyrrolidine]-2′,5′-dione(50.0 mg, 0.231 mmol, described in Intermediate 3),5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(62.0 mg, 0.231 mmol, described in Intermediate 7), EDC (53.0 mg, 0.277mmol), HOBT (42.0 mg, 0.277 mmol), and triethylamine (0.0890 mL, 0.509mmol) were stirred for 16 h at ambient temperature in DMF (2 mL). Thereaction mixture was partitioned between saturated NaHCO₃ (3 mL) andEtOAc (5 mL). The layers were separated and the organic layer was washedwith H₂O (3 mL) and 10% citric acid (3 mL), then dried over Na₂SO₄,filtered, and concentrated in vacuo. Purification of the crude productby silica gel chromatography, eluting with a gradient ofCH₂Cl₂:MeOH-100:0 to 90:10, gave the title compound. MS: 7/z=468 (M+1).HRMS: m/z=468.1671; calculated m/z=468.1667 for C₂₆H₂₂N₅O₄.

EXAMPLE 2

(±)-N-(4′-Chloro-6′-oxo-1,3,6′,7′-tetrahydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-5-yl)-2-(2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetamide

Essentially following the procedure described for Example 1, but usingIntermediate 6 in place of Intermediate 3, the title compound wasobtained. MS: m/z=538 (M+1). HRMS: m/z=538.1376; calculated m/z=538.1389for C₂₈H₂₁ClN₇O₃.

EXAMPLE 3

(±)-2-(2-Oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)-N-(6′-oxo-1,3,6′,7′-tetrahydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-5-yl)acetamide

Essentially following the procedure described for Example 1, but usingIntermediate 5 in place of Intermediate 3, the title compound wasobtained. MS: m/z=504 (M+1). HRMS: m/z=504.1769; calculated771/Z=504.1778 for C₂₈H₂₂N₇O₃.

EXAMPLE 4

(±)-N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-indol]-5-yl)-2-[2-oxo-3-(1,3-thiazol-2-yl)-2,3-dihydro-1H-benzimidazol-1-yl]acetamide

Essentially following the procedure described for Example 1, but usingIntermediate 2 in place of Intermediate 3, and Intermediate 33 in placeof Intermediate 7, the title compound was obtained. MS: m/z=508 (M+1).HRMS: m/z=508.1425; calculated m/z=508.1438 for C₂₈H₂₁N₅O₃S.

EXAMPLES 5-10

Essentially following the procedure outlined for Example 1, but usingIntermediate 1 in place of Intermediate 3, the compounds listed in Table2 were prepared. The requisite carboxylic acids were commerciallyavailable, described in the literature, synthesized according tomethodology described herein (vide supra), or readily synthesized by oneskilled in the art of organic synthesis. In some cases, straightforwardprotecting group strategies were applied.

TABLE 2

MS Example R^(b) (M + 1) 5

454 6

477 7

462 8

545 9

445 10

527

EXAMPLES 11-41

Essentially following the procedure outlined for Example 1, but usingIntermediate 4 in place of Intermediate 3, the compounds listed in Table3 were prepared. The requisite carboxylic acids were commerciallyavailable, described in the literature, synthesized according tomethodology described herein (vide supra), or readily synthesized by oneskilled in the art of organic synthesis. In some cases, straightforwardprotecting group strategies were applied.

TABLE 3

Example R^(b) MS (M + 1) 11

503 12

504 13

504 14

518 15

504 16

555 17

587 18

576 19

562 20

526 21

540 22

539 23

539 24

571 25

496 26

563 27

504 28

567 29

495 30

507 31

509 32

591 33

495 34

561 35

526 36

511 37

509 38

557 39

570 40

558 41

482 42

522 43

508 44

497

EXAMPLE 45

cis-2-[3-(1-Oxidotetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]-N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-indol]-5-yl)acetamide,enantiomer B

Sodium periodate (9 mg, 0.043 mmol) was added to a solution ofN-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)-2-[2-oxo-3-(tetrahydro-2H-thiopyran-4-yl)-2,3-dihydro-1H-benzimidazol-1-yl]acetamide,enantiomer B (19 mg, 0.036 mmol, described in Example 35) in H₂O (1 mL).After 20 h, the reaction mixture was purified directly by HPLC using areversed phase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H-90:10:0.1 to 5:95:0.1 to provide the title compound.MS: n7/z=542 (M+1). HRMS: m/z=542.1846; calculated m/z=542.1857 forC₂₉H₂₈N₅O₄S.

EXAMPLE 46

trans-2-[3-(1-Oxidotetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]-N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-indol]-5-yl)acetamide,enantiomer B

Following the procedure outlined for Example 45, the title compound wasobtained as a white solid. MS: m/z=542 (M+1). HRMS: m/z=542.1847;calculated m/z=542.1857 for C₂₉H₂₈N₅O₄S.

EXAMPLE 47

cis-2-(1′-Oxido-2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)-N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)acetamide,enantiomer B

Following the procedures outlined for Example 45, but usingN-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)-2-(2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)acetamide,enantiomer B (described in Example 36) in place of(±)-N-(2′-oxo-1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)-2-[2-oxo-3-(tetrahydro-2H-thiopyran-4-yl)-2,3-dihydro-1H-benzimidazol-1-yl]acetamide,enantiomer B (described in Example 35), the title compound was obtainedas a white solid. MS: m/z=527 (M+1). HRMS: m/z=527.1726; calculatedm/z=527.1748 for C₂₉H₂₇N₄O₄S.

EXAMPLE 48

trans-2-(1′-Oxido-2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)-N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)acetamide,enantiomer B

Following the procedure outlined for Example 47, the title compound wasobtained as a white solid. MS: m/z=527 (M+1). HRMS: m/z=527.1727;calculated m/z=527.1748 for C₂₉H₂₇N₄O₄S.

EXAMPLE 49

2-[3-(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]-N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)acetamide,enantiomer B

OXONE® (35.0 mg, 0.057 mmol) in H₂O (1 mL) was added to a solution ofN-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)-2-[2-oxo-3-(tetrahydro-2H-thiopyran-4-yl)-2,3-dihydro-1H-benzimidazol-1-yl]acetamide,enantiomer B (10.0 mg, 0.019 mmol, described in Example 35) inisopropanol (1 mL) and CHCl₃ (1 mL). After 20 h, the reaction mixturewas purified directly by HPLC using a reversed phase C18 column andeluting with a gradient of H₂O:CH₃CN:CF₃CO₂H-90:10:0.1 to 5:95:0.1 toprovide the title compound. MS: m/z=558 (M+1). HRMS: m/z=558.1783;calculated m/z=558.1806 for C₂₉H₂₇N₅O₅S

EXAMPLE 50

2-(5-Bromo-1′1′-dioxido-2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)-N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)acetamideenantiomer B

Following the procedures outlined for Example 49, but using2-(5-bromo-2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)-N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-h]pyridin]-5-yl)acetamide,enantiomer B (described in Example 32) in place ofN-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)-2-[2-oxo-3-(tetrahydro-2H-thiopyran-4-yl)-2,3-dihydro-1H-benzimidazol-1-yl]acetamide,enantiomer B (described in Example 35), the title compound was obtainedas a white solid. MS: m/z=621 (M+1). HRMS: m/z=621.0794; calculatedm/z=621.0802 for C₂₉H₂₆BrN₄O₅S

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inthe responsiveness of the mammal being treated for any of theindications with the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compounds selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims which follow and that such claims be interpreted as broadlyas is reasonable.

1. A compound of formula I:

wherein: B is a bicycloheterocycle selected from the group consistingof:

where T, U, V, W, X and Y are each independently a carbon atom or anitrogen atom, wherein no more than two of T, U, V and W, and no morethan three of T, U, V, W, X and Y, are a nitrogen atoms, B isunsubstituted or substituted with 1-5 substituents each independentlyselected from R¹, R², R^(3a) and R³b, wherein R¹, R², R^(3a) and R^(3b)are independently selected from: (1) —C₁₋₆alkyl, which is unsubstitutedor substituted with 1-5 substituents each independently selected from:(a) fluoro, (b) —CO₂R⁹, wherein R⁹ is independently selected from:—C₁₋₄alkyl and —C₃₋₆cycloalkyl, and (c) —CONR^(10a)R^(11a), whereinR^(10a) and R¹¹ are each independently selected from: hydrogen and—C₁₋6alkyl, (2) phenyl or heterocycle, wherein heterocycle is selectedfrom: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolidinyl,thiazolyl, tetrahydrofuryl, and tetrahydrothiopyranyl, which phenyl orheterocycle is unsubstituted or substituted with 1-5 substituents eachindependently selected from: (a) —C₁₋6alkyl, which is unsubstituted orsubstituted with 1-3 fluoro, (b) halo, (c) —CO₂R^(9,) (d) —(CO)R⁹, (e)oxo, (f) —S—C₁₋₄alkyl, (g) —S(O)—C₁₋₄alkyl, and (h) —SO₂—C₁₋₄alkyl, (3)halo, (4) —NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are each independently selectedfrom: hydrogen, and —COR⁹; or R^(3a) and R^(3b) and the carbon atom towhich they are attached are joined to form a ring selected fromcyclohexyl, piperidinyl, tetrahydropyranyl, and tetrahydrothiopyranyl,which ring is unsubstituted or substituted with 1-5 substituents eachindependently selected from: (a) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-3 substituents each independently selected from:halo, (b) hydroxy, (c) —CO₂R⁹, and (d) oxo; A¹ and A² are eachindependently selected from: a bond and —CR¹³R¹⁴—, wherein R¹³ and R¹⁴are hydrogen, wherein one of A¹ and A² is optionally absent; J isindependently selected from: ═C(R^(6a))—, —CR¹³R¹⁴— and —C(═O)—; K isindependently selected from: ═C(R^(6b))—, —CR¹³R¹⁴—, —C(═O)—; R⁴ isindependently selected from: hydrogen, C₁₋₆ alkyl which is unsubstitutedor substituted with 1-6 fluoro, C₅₋₆ cycloalkyl, benzyl and phenyl;R^(5a), R^(5b) and R^(5c) are hydrogen; R^(6a) and R^(6b) are hydrogen;or R^(6a) and R^(6b) and the atom(s) to which they are attached arejoined to form a ring selected from phenyl, pyridyl and pyrimidinyl,which ring is unsubstituted or substituted with 1-5 substituentsindependently selected from halo; m is 1; n is 1; and pharmaceuticallyacceptable salts thereof and individual enantiomers and diastereomersthereof.
 2. The compound of claim 1, of the formula Ic:

and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.
 3. The compound of claim 1, of the formulaIe:

and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.
 4. The compound of claim 1, of the formulaIf:

and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.
 5. The compound of claim 1, of the formulaIg:

and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.
 6. The compound of claim 1, wherein B isselected from:

where B is unsubstituted or substituted with 1-5 substituents selectedfrom R¹, R², R^(3a).
 7. The compound of claim 1, wherein B is selectedfrom: 2-oxobenzimidazolinyl, indolyl, indolinyl, 2-oxoindolinyl,2-oxoazabenzimidazolinyl and azaindolyl.
 8. The compound of claim 1,wherein J is selected from: ═C(R^(6a))— and —CH₂—.
 9. The compound ofclaim 1, wherein K is selected from: ═C(R^(6b))—, —CH₂—, and —C(═O)—.10. The compound of claim 1, wherein R⁴ is selected from: hydrogen and—C₁₋₆alkyl which is unsubstituted or substituted with fluoro.
 11. Acompound selected from:

and pharmaceutically acceptable salts and individual diastereomersthereof.
 12. A pharmaceutical composition which comprises an inertcarrier and the compound of claim
 1. 13. A pharmaceutical compositioncomprising: a therapeutically effective amount of the compound of claim1 or a pharmaceutically acceptable salt thereof; and a therapeuticallyeffective amount of a second agent selected from serotonin agonists,analgesics, anti-inflammatory agents, and anticonvulsants.
 14. Thecomposition of claim 13, wherein said second agent is selected from a5HT_(1B/1D) agonist, a 5HT_(1D) agonist, and a 5HT_(1F) agonist.
 15. Thecomposition of claim 14, wherein said second agent is selected fromrizatriptan, sumatriptan, naratriptan, zolmitriptan, almotriptan,eletriptan, avitriptan, frovatriptan, LY334370 and PNU-142633.
 16. Thecomposition of claim 13, wherein said second agent is selected fromergotamine and dihydroergotamine.
 17. The composition of claim 13,wherein said second agent is aspirin or acetaminophen.
 18. Thecomposition of claim 13, wherein said second agent is a glucocorticoid.19. The composition of claim 13, wherein said second agent is anon-steroidal anti-inflammatory agent.
 20. The composition of claim 19,wherein said second agent is selected from ibuprofen, ketoprofen,fenoprofen, naproxen, indomethacin, sulindac, meloxicam, piroxicam,tenoxicam, lornoxicam, ketorolac, etodolac, mefenamic acid, meclofenamicacid, flufenamic acid, tolfenamic acid, diclofenac, oxaprozin, apazone,nimesulide, nabumetone, tenidap, etanercept, tolmetin, phenylbutazone,oxyphenbutazone, diflunisal, salsalate, olsalazine and sulfasalazine.21. The composition of claim 13, wherein said second agent is ananticonvulsant selected from topiramate, zonisamide, divalproex sodium,pregabalin, gabapentin, levetiracetam, lamotrigine and tiagabine.
 22. Apharmaceutical composition comprising: a therapeutically effectiveamount of the compound of claim 1 or a pharmaceutically acceptable saltthereof; and a therapeutically effective amount of a second agentselected from angiotensin II antagonists, angiotensin I antagonists,angiotensin converting enzyme inhibitors, and renin inhibitors.
 23. Thecomposition of claim 22, wherein said second agent is selected fromlosartan, candesartan, candesartan cilexetil, irbesartan, valsartan,eprosartan, telmisartan, olmesartan, medoxomil, captopril, benazepril,quinapril, perindopril, ramipril, trandolapril, lisinopril, andenalapril.
 24. A pharmaceutical composition comprising: atherapeutically effective amount of the compound of claim 1 or apharmaceutically acceptable salt thereof; and a therapeuticallyeffective amount of a second agent selected from anti-anxiety agents andneuroleptics.
 25. The composition of claim 24, wherein said second agentis selected from, diazepam, alprazolam, chlordiazepoxide, olanzapine,droperidol, prochlorperazine, chlorpromazine and quetiapine.
 26. Apharmaceutical composition comprising: a therapeutically effectiveamount of the compound of claim 1 or a pharmaceutically acceptable saltthereof; and a therapeutically effective amount of a second agentselected from beta-blockers and calcium channel blockers.
 27. Thecomposition of claim 26, wherein said second agent is selected fromtimolol, propanolol, atenolol, metoprolol, nadolol, flunarizine,diltiazem, amlodipine, felodipine, nisolipine, isradipine, nimodipine,lomerizine, verapamil, nifedipine, prochlorperazine and civamide.
 28. Apharmaceutical composition comprising: a therapeutically effectiveamount of the compound of claim 1 or a pharmaceutically acceptable saltthereof; and a therapeutically effective amount of a second agentselected from anti-depressants, selective serotonin reuptake inhibitors,and NE reuptake inhibitors.
 29. The composition of claim 28, whereinsaid second agent is selected from amitriptyline, nortriptyline,clomipramine, imipramine, venlafaxine, doxepin, protriptyline,desipramine, trimipramine, fluoxetine, paroxetine, sertraline,duloxetine, escitalopram, and citalopram.
 30. A pharmaceuticalcomposition comprising: a therapeutically effective amount of thecompound of claim 1 or a pharmaceutically acceptable salt thereof; and atherapeutically effective amount of a second agent selected frombotulinum toxins A or B.
 31. A pharmaceutical composition comprising: atherapeutically effective amount of the compound of claim 1 or apharmaceutically acceptable salt thereof; and a therapeuticallyeffective amount of a second agent selected from vanilloid receptorantagonists, adenosine 1 antagonists, NR2B antagonists, substance Pantagonists, granzyme B inhibitors, endothelin antagonists,norepinephrin precursors, nitric oxide synthase inhibitors,neuroleptics, bradykinin antagonists, gap junction inhibitors, AMPA/KAantagonists, sigma receptor agonists, chloride channel enhancers,monoamine oxidase inhibitors, opioid agonists, and leukotriene receptorantagonists.
 32. The composition of claim 31, wherein said second agentis selected from montelukast and zafirlukast.
 33. The composition ofclaim 31, wherein said second agent is aprepitant.
 34. A pharmaceuticalcomposition comprising: a therapeutically effective amount of thecompound of claim 1 or a pharmaceutically acceptable salt thereof; and atherapeutically effective amount of a second agent selected from thegroup consisting of anti-emetics, prokinetics, and histamine H1antagonists.